Compounds for the treatment of proliferative disorders

ABSTRACT

The invention relates to compounds of structural formula (I): 
     
       
         
         
             
             
         
       
         
         
           
             or a pharmaceutically acceptable salt, solvate, clathrate, and prodrug thereof, wherein R a , R b , and R 2  are defined herein. These compounds inhibit tubulin polymerization and/or target vasculature and are useful for treating proliferative disorders, such as cancer.

RELATED APPLICATIONS

This application is a continuation application of U.S. application Ser.No. 13/558,886, filed Jul. 26, 2012, which is a continuation applicationof U.S. application Ser. No. 12/883,883, filed Sep. 16, 2010 and nowU.S. Pat. No. 8,269,017, which is a continuation application of Ser. No.11/355,922, filed Feb. 16, 2006 and now U.S. Pat. No. 7,884,094, whichclaims benefit of U.S. Provisional Application No. 60/653,890, filedFeb. 17, 2005; U.S. Provisional Application No. 60/660,112, filed Mar.8, 2005; and U.S. Provisional Application No. 60/733,912, filed Nov. 4,2005. The entire contents of each of the aforementioned applications areincorporated herein by reference in their entirety.

FIELD OF THE INVENTION

This invention relates to biologically active chemical compounds, namelyisoxazole derivatives that may be used for treating or preventingproliferative disorders.

BACKGROUND OF THE INVENTION

Many chemotherapeutic methods are now available to be used in thetreatment of cancer. One of the most successful methods is the use ofanti-mitotic agents which interfere with the assembly or disassembly ofmicrotubules. Since microtubule assemble and disassemble is necessaryfor mitosis, inhibition of either the assembly or disassembly ofmicrotubules interferes with cell proliferation. Thus, compounds thatinhibit the assembly of microtubule are useful in treating diseases orconditions which are caused or exasperated by rapid or abnormal cellproliferation, such as cancer.

Several anti-mitotic agents have had considerable clinical success. Forexample, the following vinca alkaloids which inhibit microtubuleassembly have proved clinically successful: Vincristine has beensuccessfully used to treat hematological malignancies and non-small-celllung carcinoma; Vinblastine has been successfully used to treathematological malignancies, testicular carcinomas and non-small-celllung carcinoma; and Vinorelbine has been successfully used to treathematological malignancies, breast carcinomas and non-small-cell lungcarcinoma. In addition, taxanes which inhibit microtubule disassemblehave also proved to be clinically successful. For example, Paclitaxelhas been successful in treating breast, ovarian and non-small-cell lungcarcinomas; and Docetaxel has been successful in treating breast andnon-small-cell lung carcinomas.

Despite these successes, available anti-mitotic agents are inadequatefor a number of reasons. For example, paclitaxel, docetaxel andvincristine are associated with significant neuropathy which can limittheir use in repeat courses of therapy. In addition, both the vincaalkaloids and taxanes are good substrates for the 170 kDa P-glycoprotein(Pgp) efflux pump found in most multi-drug resistant cells. This proteinpumps a drug out of the tumor cells causing the tumor cells to becomeresistant to treatment. Once a patient's cancer has become multi-drugresistant, there is typically little that can be done to halt or retardfurther progression of the disease.

There is therefore still a need for new drugs which overcome one or moreof the aforementioned shortcomings of drugs currently used in thetreatment of cancer.

Desirable properties of new anti-cancer drugs therefore include a goodtherapeutic index, efficacy against tumors that are currentlyuntreatable or poorly treatable, efficacy against multi-drug resistanttumors and/or reduced side effects.

SUMMARY OF THE INVENTION

This invention meets the above-mentioned needs by providing certainisoxazole derivatives that inhibit tubulin polymerization. Compounds ofthe invention are also capable of vascular targeting, in particular,blocking, occluding, or otherwise disrupting blood flow inneovasculature. These compounds are particularly useful for treating orpreventing proliferative disorders, such as cancer.

In one embodiment, the invention relates to compounds of formula (I):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein:

one of R_(a) or R_(b) is —H and the other is an optionally substitutedaryl, or an optionally substituted heteroaryl; and

R₂ is an optionally substituted phenyl, an optionally substituted2,3-dihydro-benzo[1,4]dioxinyl, an optionally substitutedbenzo[1,3]dioxolyl, an optionally substituted biphenyl, an optionallysubstituted 4-pyridinyl-phenyl, an optionally substituted quinolinyl, anoptionally substituted isoquinolinyl, an optionally substituted1H-indolyl, an optionally substituted pyridinyl, an optionallysubstituted oxazolyl, an optionally substituted isoxazolyl, anoptionally substituted thiazolyl, an optionally substitutedisothiazolyl, an optionally substituted imidazolyl, an optionallysubstituted pyrrolyl, an optionally substituted pyrazolyl, an optionallysubstituted furanyl, an optionally substituted thiophenyl, an optionallysubstituted thiadiazolyl, an optionally substituted oxadiazolyl, anoptionally substituted chromanyl, an optionally substitutedisochromanyl, an optionally substituted pyridazinyl, an optionallysubstituted pyrimidinyl, an optionally substituted pyrazinyl, anoptionally substituted benzothiophenyl, an optionally substituted2,3-dihydro-benzothiophenyl, an optionally substituted benzofuranyl, anoptionally substituted 2,3-dihydro-benzofuranyl, an optionallysubstituted 1H-benzoimidazolyl, an optionally substitutedbenzothiazolyl, an optionally substituted benzooxazolyl, an optionallysubstituted 1H-benzotriazolyl, an optionally substituted 1H-indazolyl,an optionally substituted 9H-purinyl, an optionally substitutedpyrrolopyrimidinyl, an optionally substituted pyrrolopyrazinyl, anoptionally substituted pyrrolopyridazinyl, an optionally substitutedimidazopyrazinyl, or an optionally substituted imidazolpyridazinyl.

In another embodiment, the invention relates to compounds of formula(II):

or a pharmaceutically acceptable salt, solvate, clathrate, and prodrugthereof, wherein:

one of R_(c) or R_(d) is —H and the other is an optionally substitutedheteroaryl, an unsubstituted phenyl, or a substituted phenyl representedby one of the following formulas:

R₄ is an optionally substituted aryl or an optionally substitutedheteroaryl;

R₁₈, R₁₉, R₂₂, and R₂₃, are each, independently, halo, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, an optionally substituted heteraralkyl,cyano, nitro, guanadino, a haloalkyl, a haloalkoxy, a heteroalkyl, —OR₇,—NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—OP(O)(OR₇)₂, —SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇,—S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁;

R₂₀ is an optionally substituted alkyl, an optionally substitutedalkenyl, an optionally substituted alkynyl, an optionally substitutedcycloalkyl, an optionally substituted cycloalkenyl, an optionallysubstituted heterocyclyl, an optionally substituted aryl, an optionallysubstituted heteroaryl, an optionally substituted aralkyl, an optionallysubstituted heteraralkyl, cyano, nitro, guanadino, a haloalkyl, ahaloalkoxy, a heteroalkyl, —OR₁₇, —NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇,—C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇,—OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁;

R₂₁ is halo, an optionally substituted alkyl, an optionally substitutedalkenyl, an optionally substituted alkynyl, an optionally substitutedcycloalkyl, an optionally substituted cycloalkenyl, an optionallysubstituted heterocyclyl, an optionally substituted aryl, an optionallysubstituted heteroaryl, an optionally substituted aralkyl, an optionallysubstituted heteraralkyl, cyano, nitro, guanadino, a haloalkyl, ahaloalkoxy, a heteroalkyl, —OR₁₇, —NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇,—C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂, SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇,—OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁;

R₇ and R₈, for each occurrence, are, independently, —H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, or an optionally substitutedheteraralkyl;

R₁₀ and R₁₁, for each occurrence, are independently —H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, or an optionally substitutedheteraralkyl; or R₁₀ and R₁₁, taken together with the nitrogen to whichthey are attached, form an optionally substituted heterocyclyl or anoptionally substituted heteroaryl;

R₁₇, for each occurrence, is independently, an optionally substitutedalkyl, an optionally substituted alkenyl, an optionally substitutedalkynyl, an optionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl; and

p is 1 or 2.

Compounds of the invention or pharmaceutically acceptable salts,solvates, clathrates, or prodrugs thereof are potent antimitotic agentswhich inhibiting tubulin polymerization, and thus can inhibitmicrotubule growth. In order for cells to undergo mitosis, microtubulesmust be able to assemble and disassemble, in a process known as dynamicinstability. Thus, in one embodiment, the compounds of the invention canbe used to inhibit tubulin polymerization in a cell by contacting thecell with an effective amount of a compound of the invention or apharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof.

In another embodiment, compounds of the invention can be used to inhibittubulin polymerization in a subject by administering to the subject aneffective amount of a compound of the invention or a pharmaceuticallyacceptable salt, solvate, clathrate, or prodrug thereof.

Compounds of the invention or pharmaceutically acceptable salts,solvates, clathrates, or prodrugs thereof are vascular targeting agentswhich can be used to block, occlude, or otherwise disrupt blood flow inneovasculature, and thus lead to destruction of vasculature. Thus in oneembodiment, compounds of the invention can be used to block, occlude, orotherwise disrupt blood flow in neovasculature by contacting theneovasculature with an effective amount of a compound of the inventionor a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof.

In another embodiment, compounds of the invention can be used to block,occlude, or otherwise disrupt blood flow in neovasculature of a subjectby administering to the subject an effective amount of a compound of theinvention or a pharmaceutically acceptable salt, solvate, clathrate, orprodrug thereof.

Since the compounds of the invention disrupt mitosis by inhibitingtubulin polymerization, they are particularly useful in treating orpreventing proliferative disorders, such as cancer. Therefore, in oneembodiment, compounds of the invention or pharmaceutically acceptablesalts, solvates, clathrates, or prodrugs thereof can be used to treat orprevent a proliferative disorder in a subject by administering to thesubject an effective amount of a compound of the invention or apharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof.

All of the methods of this invention may be practice with a compound ofthe invention alone, or in combination with other agents, such as otheranti-cancer agents.

As will be described in detail below, compounds of the inventionovercome or ameliorated some of the limitation of known anti-mitoticagents. In particular, compounds of the invention are cytotoxic inmultidrug resistant cells, and thus may be useful for treating cancersthat have become resistant to other therapies.

DESCRIPTION OF THE FIGURES

FIG. 1 shows the cytotoxic effects of compounds of the invention onhepatocytes compared to untreated cells and to known cancer drugs Taxoland 17AAG.

FIG. 2 shows the cytotoxic effects of compounds of the invention onhepatocytes compared to untreated cells and to known cancer drug 17AAG.

FIG. 3 shows the microtubule network of Chinese Hamster Ovary (CHO)cells transfected with a vector encoding α-tubulin-YFP after they havebeen treated with DMSO.

FIG. 4 shows the microtubule network of CHO cells transfected with avector encoding α-tubulin-YFP after they have been treated with 0.1 μMTaxol.

FIG. 5 shows the microtubule network of CHO cells transfected with avector encoding α-tubulin-YFP after they have been treated with 0.1 μMCompound 1.

FIG. 6 shows the microtubule network of CHO cells transfected with avector encoding α-tubulin-YFP after they have been treated with 0.1 μMCompound 3.

FIG. 7 shows the microtubule network of CHO cells transfected with avector encoding α-tubulin-YFP after they have been treated with 0.1 μMCompound 6.

FIG. 8A shows the microtubule network of CV-1 cells 24 hrs aftertreatment with DMSO. CV-1 cells are known to be resistant to thedepolymerization effects of colchicines and vincristine.

FIG. 8B shows the microtubule network of CV-1 cells 24 hrs aftertreatment with Compound 3.

FIG. 8C shows the microtubule network of CV-1 cells 24 hrs aftertreatment with colchicine.

FIG. 8D shows the microtubule network of CV-1 cells 24 hrs aftertreatment with vincristine.

FIG. 8E shows a magnified view of the microtubule network of CV-1 cells24 hrs after treatment with Compound 3.

FIG. 9A shows the microtubule network of CV-1 cells 48 hrs aftertreatment with DMSO.

FIG. 9B shows the microtubule network of CV-1 cells 48 hrs aftertreatment with Compound 3.

FIG. 9C shows the microtubule network of CV-1 cells 48 hrs aftertreatment with colchicine.

FIG. 9D shows the microtubule network of CV-1 cells 48 hrs aftertreatment with vincristine.

FIG. 9E shows a magnified view of the microtubule network of CV-1 cells48 hrs after treatment with Compound 3.

FIG. 10A shows the microtubule network of CV-1 cells 72 hrs aftertreatment with DMSO.

FIG. 10B shows the microtubule network of CV-1 cells 72 hrs aftertreatment with Compound 3.

FIG. 10C shows the microtubule network of CV-1 cells 72 hrs aftertreatment with colchicine.

FIG. 10D shows the microtubule network of CV-1 cells 72 hrs aftertreatment with vincristine.

FIG. 10E shows a magnified view of the microtubule network of CV-1 cells72 hrs after treatment with Compound 3.

FIG. 11 shows the results of a nude mouse xenograft study to determinethe effect of Compound 3 on the in vivo growth rate of the human tumorcell line MDA-MB-435S. Tumor bearing animals (10 mice/group) were i.v.injected 3 times per week for a total of 10 doses (hatched bar) and theaverage tumor volumes for each group (+/−SEM) were determined every 2-4days. Treatment with doses of 12.5 and 25 mg/kg body weight of Compound3 caused tumor regression, whereas a dose of 7.5 mg/kg body weight ofpaclitaxel did not.

FIG. 12 shows percent change in body weight of animals during the studypresented in FIG. 11. Treatment with Compound 3 did not cause overttoxicity in a nude mouse xenograft model using the human tumor cell lineMDA-MB-435S. Tumor bearing animals (10 mice/group) were i.v. injected 3times per week for a total of 10 doses (hatched bar) and the cumulativeaverage percent changes in body weights for each group relative to thestart of dosing (+/−SEM) were determined every 1-3 days. Treatment withdoses of 6.25, 12.5 and 25 mg/kg body weight of Compound 3 was notovertly toxic, as indicated by the minimal effects on the animal bodyweights in the test article-treated versus vehicle-treated groups.

FIG. 13 shows the results of a nude mouse xenograft study to determinethe effect of Compound 3 on the in vivo growth rate of the human tumorcell line RERF-LC-Al. Tumor bearing animals (8 mice/group) were i.v.injected 3 times per week for a total of 8 doses (hatched bar) and theaverage tumor volumes for each group (+/−SEM) were determined every 3-4days. Treatment with 25 mg/kg body weight of Compound 3 inhibited tumorgrowth to a similar degree to what was observed with a dose of 12.5mg/kg body weight of paclitaxel.

FIG. 14 shows percent change in body weight of animals during the studypresented in FIG. 13. Treatment with Compound 3 did not cause overttoxicity in a nude mouse xenograft model using the human tumor cell lineRERF-LC-Al. Tumor bearing animals (8 mice/group) were i.v. injected 3times per week for a total of 9 doses (hatched bar) and the cumulativeaverage percent changes in body weights for each group relative to thestart of dosing (+/−SEM) were determined every 1-3 days. Treatment withdoses of 25 mg/kg body weight of Compound 3 was not overtly toxic, asindicated by the minimal effects on the animal body weights in the testarticle-treated versus vehicle-treated groups.

FIG. 15 shows the results of a nude mouse xenograft study to determinethe effects of Compounds 169 and 174 on the in vivo growth rate of thehuman tumor cell line MDA-MB-435S. Tumor bearing animals (8 mice/group)were i.v. injected 1 time per week for a total of 3 doses (arrowheads)and the median tumor volumes for each group (error bars represent SEM)were determined every 3-4 days. Treatment with doses of 2 mg/kg bodyweight of Compound 169 and 4.55 mg/kg body weight of Compound 174substantially inhibited tumor growth.

FIG. 16 shows percent change in body weight of animals during the studypresented in FIG. 15. Treatment with Compounds 169 and 174 did not causeovert toxicity in a nude mouse xenograft model using the human tumorcell line MDA-MB-435S (data derived from the same study presented inFIG. 15). Tumor bearing animals (8 mice/group) were i.v. injected 1 timeper week for a total of 3 doses (arrowheads) and the cumulative averagepercent changes in body weights for each group relative to the start ofdosing were determined every 1-4 days (error bars not shown forclarity). Treatment with doses of 2 and 1 mg/kg body weight of Compound169 and 4.55 and 2.28 mg/kg body weight of Compound 174 were not overtlytoxic, as indicated by the minimal effects on the animal body weights inthe test article-treated versus vehicle-treated groups.

FIG. 17 shows the results of a nude mouse xenograft study to determinethe effect of Compound 178 on the in vivo growth rate of the human tumorcell line MDA-MB-435S. Tumor bearing animals (8 mice/group) were i.v.injected with Compound 178 3 times per week for a total of 3 doses at 25mg/kg body weight (closed arrowheads), followed by 3 times per week fora total of 3 doses at 37.5 mg/kg body weight (open arrowheads), followedby 3 times per week for a total of 3 doses at 50 mg/kg body weight(arrows). The median tumor volumes for each group (error bars representSEM) were determined every 3-5 days. Compound 178 began to show moderateefficacy at doses of 37.5 and 50 mg/kg body weight.

FIG. 18 shows percent change in body weight of animals during the studypresented in FIG. 17. Treatment with Compound 178 did not cause overttoxicity in a nude mouse xenograft model using the human tumor cell lineMDA-MB-435S (data derived from the same study presented in FIG. 17).Tumor bearing animals (8 mice/group) were i.v. injected with Compound178 3 times per week for a total of 3 doses at 25 mg/kg body weight(closed arrowheads), followed by 3 times per week for a total of 3 dosesat 37.5 mg/kg body weight (open arrowheads), followed by 3 times perweek for a total of 3 doses at 50 mg/kg body weight (arrows). Thecumulative average percent change in body weights for each grouprelative to the start of dosing (error bars represent SEM) weredetermined every 1-3 days. Treatment with doses of 25, 37.5 or 50 mg/kgbody weight of Compound 178 were not overtly toxic, as indicated by theminimal effects on the animal body weights in the test article-treatedversus vehicle-treated groups.

FIG. 19 shows the effect of Compound 3 on the in vivo induction of tumornecrosis in an EMT6 mouse mammary carcinoma tumor model in nude mice.Tumor-bearing animals (5 mice/group) were given a single i.v. bolusinjection of either vehicle or Compound 3, and at the indicated timepoints following dosing the tumors were excised and processed forhistology. Light microscopy was used to quantitate the average area ofnecrosis as a percent of total area in tumor sections from eachtreatment group (error bars represent SEM). Treatment with a single doseof 25 mg/kg body weight of Compound 3 resulted in a near maximal 2.4fold increase in tumor necrosis at 4 hours following drug treatment.

FIG. 20A shows shows the microtubule network of CV-1 cells 24 hrs aftertreatment with DMSO.

FIG. 20B shows the microtubule network of CV-1 cells 24 hrs aftertreatment with 1 nM of Compound 249.

FIG. 20C shows the microtubule network of CV-1 cells 24 hrs aftertreatment with 10 nM of Compound 249.

FIG. 20D shows the microtubule network of CV-1 cells 24 hrs aftertreatment with 100 nM of Compound 249.

FIG. 20E shows the microtubule network of CV-1 cells 24 hrs aftertreatment with 1000 nM of Compound 249.

FIG. 21A shows the microtubule network of HUVEC cells 24 hrs aftertreatment with DMSO.

FIG. 21B shows the microtubule network of HUVEC cells 24 hrs aftertreatment with 1 nM of Compound 249.

FIG. 21C shows the microtubule network of HUVEC cells 24 hrs aftertreatment with 5 nM of Compound 249.

FIG. 21D shows the microtubule network of HUVEC cells 24 hrs aftertreatment with 10 nM of Compound 249.

FIG. 21E shows the microtubule network of HUVEC cells 24 hrs aftertreatment with 50 nM of Compound 249.

FIG. 21F shows the microtubule network of HUVEC cells 24 hrs aftertreatment with 100 nM of Compound 249.

FIG. 22 shows a nude mouse tumor study to determine the effect ofCompound 174 on the in vivo growth rate of the allogeneic mouse mammarycarcinoma cell line EMT6. Tumor-bearing animals (15 mice/group) weregiven a single i.v. bolus injection of either vehicle or Compound 174,and changes in median tumor volumes (error bars represent SEM) for eachgroup were determined after 3 days. Treatment with doses of 4.55 and3.22 mg/kg body weight of Compound 174 substantially inhibited tumorgrowth. The largest average percent change in body weight observed forany group in this study was −7.3% (+/−0.9 SEM) one day after dosingCompound 174 at 4.55 mg/kg body weight. No individual animal lost>11%body weight at any point over the course of the study.

FIG. 23 shows a study examining the vascular disrupting activity ofCompound 174 as measured by the Evans Blue dye assay in the EMT6 mousemammary carcinoma tumor model conducted in nude mice. (Top)Tumor-bearing animals (8 mice/group) were given a single i.v. bolusinjection of either vehicle or Compound 174 at time 0 hr, followed by asingle i.v. bolus injection of Evan's Blue dye at time+1 hr. At +4 hrs,tumors were excised and tumor dye penetration was quantitated.Representations of black and white mice indicate animals that have beeninjected or not injected with Evan's Blue dye, respectively. (Bottom)Treatment with single doses of 4.55, 3.22 or 2.28 mg/kg body weight ofCompound 174 resulted in substantial decreases in tumor dye uptake at +4hr. A similar decrease was also observed after a single dose of 4.55mg/kg body weight of Compound 174 at +2 hr (data not shown).

DETAILED DESCRIPTION OF THE INVENTION Definitions

Unless otherwise specified, the below terms used herein are defined asfollows:

As used herein, the term an “aromatic ring” or “aryl” means a monocyclicor polycyclic-aromatic ring or ring radical comprising carbon andhydrogen atoms. Typically, aryl groups have about 6 to about 14 carbonatom ring members. Examples of suitable aryl groups include, but are notlimited to, phenyl, tolyl, anthacenyl, fluorenyl, indenyl, azulenyl, andnaphthyl, as well as benzo-fused carbocyclic moieties such as5,6,7,8-tetrahydronaphthyl. An aryl group can be unsubstituted orsubstituted with one or more substituents (including without limitationalkyl (preferably, lower alkyl or alkyl substituted with one or morehalo), hydroxy, alkoxy (preferably, lower alkoxy), alkylsulfanyl, cyano,halo, amino, and nitro. In certain embodiments, the aryl group is amonocyclic ring, wherein the ring comprises 6 carbon atoms.

As used herein, the term “alkyl” means a saturated straight chain orbranched non-cyclic hydrocarbon typically having from 1 to 10 carbonatoms. Representative saturated straight chain alkyls include methyl,ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyland n-decyl; while saturated branched alkyls include isopropyl,sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylbutyl,3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl,2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl,2,3-dimethylbutyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl,2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl,2,2-dimethylpentyl, 2,2-dimethylhexyl, 3,3-dimtheylpentyl,3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylpentyl, 3-ethylpentyl,2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl,2-methyl-3-ethylpentyl, 2-methyl-4-ethylpentyl, 2-methyl-2-ethylhexyl,2-methyl-3-ethylhexyl, 2-methyl-4-ethylhexyl, 2,2-diethylpentyl,3,3-diethylhexyl, 2,2-diethylhexyl, 3,3-diethylhexyl and the like. Alkylgroups included in compounds of this invention may be optionallysubstituted with one or more substituents. Examples of substituentsinclude, but are not limited to, amino, alkylamino, alkoxy,alkylsulfanyl, oxo, halo, acyl, nitro, hydroxyl, cyano, aryl, alkylaryl,aryloxy, arylsulfanyl, arylamino, carbocyclyl, carbocyclyloxy,carbocyclylthio, carbocyclylamino, heterocyclyl, heterocyclyloxy,heterocyclylamino, heterocyclylthio, and the like. In addition, anycarbon in the alkyl segment may be substituted with oxygen (═O), sulfur(═S), or nitrogen (═NR³², wherein R³² is —H, an alkyl, acetyl, oraralkyl). Lower alkyls are typically preferred for the compounds of thisinvention.

The term alkylene refers to an alkyl group or a cycloalkyl group thathas two points of attachment to two moieties (e.g., {—CH₂—}, —{CH₂CH₂—},

etc., wherein the brackets indicate the points of attachment). Alkylenegroups may be optionally substituted with one or more substituents.

An aralkyl group refers to an aryl group that is attached to anothermoiety via an alkylene linker. Aralkyl groups can be optionallysubstituted with one or more substituents.

The term “alkoxy,” as used herein, refers to an alkyl group which islinked to another moiety though an oxygen atom. Alkoxy groups can beoptionally substituted with one or more substituents.

The term “alkylsulfanyl,” as used herein, refers to an alkyl group whichis linked to another moiety though a divalent sulfur atom. Alkylsulfanylgroups can be optionally substituted with one or more substituents.

The term “arylsulfanyl,” as used herein, refers to an aryl group whichis linked to another moiety though a divalent sulfur atom. Arylsulfanylgroups can be optionally substituted with one or more substituents.

The term “alkyl ester” as used herein, refers to a group represented bythe formula —C(O)OR₃₂, wherein R₃₂ is an alkyl group. A lower alkylester is a group represented by the formula —C(O)OR₃₂, wherein R₃₂ is alower alkyl group.

The term “heteroalkyl,” as used herein, refers to an alkyl group whichhas one or more carbons in the alkyl chain replaced with an —O—, —S— or—NR₃₃—, wherein R₃₃ is H or a lower alkyl. Heteroalkyl groups can beoptionally substituted with one or more substituents.

The term “alkylamino,” as used herein, refers to an amino group in whichone hydrogen atom attached to the nitrogen has been replaced by an alkylgroup. The term “dialkylamino,” as used herein, refers to an amino groupin which two hydrogen atoms attached to the nitrogen have been replacedby alkyl groups, in which the alkyl groups can be the same or different.Alkylamino groups and dialkylamino groups can be optionally substitutedwith one or more substituents.

As used herein, the term “alkenyl” means a straight chain or branched,hydrocarbon radical typically having from 2 to 10 carbon atoms andhaving at least one carbon-carbon double bond. Representative straightchain and branched alkenyls include vinyl, allyl, 1-butenyl, 2-butenyl,isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl,1-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, 1-hexenyl, 2-hexenyl,3-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 2-octenyl,3-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 2-decenyl,3-decenyl and the like. Alkenyl groups can be optionally substitutedwith one or more substituents.

As used herein, the term “alkynyl” means a straight chain or branched,hydrocarbon radical typically having from 2 to 10 carbon atoms andhaving at lease one carbon-carbon triple bond. Representative straightchain and branched alkynyls include acetylenyl, propynyl, 1-butynyl,2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl, 4-pentynyl,-1-hexynyl, 2-hexynyl, 5-hexynyl, 1-heptynyl, 2-heptynyl, 6-heptynyl,1-octynyl, 2-octynyl, 7-octynyl, 1-nonynyl, 2-nonynyl, 8-nonynyl,1-decynyl, 2-decynyl, 9-decynyl and the like. Alkynyl groups can beoptionally substituted with one or more substituents.

As used herein, the term “cycloalkyl” means a saturated, mono- orpolycyclic alkyl radical typically having from 3 to 14 carbon atoms.Representative cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, adamantly,decahydronaphthyl, octahydropentalene, bicycle[1.1.1]pentanyl, and thelike. Cycloalkyl groups can be optionally substituted with one or moresubstituents.

As used herein, the term “cycloalkenyl” means a cyclic non-aromaticalkenyl radical having at least one carbon-carbon double bond in thecyclic system and typically having from 5 to 14 carbon atoms.Representative cycloalkenyls include cyclopentenyl, cyclopentadienyl,cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl,cycloheptatrienyl, cyclooctenyl, cyclooctadienyl, cyclooctatrienyl,cyclooctatetraenyl, cyclononenyl, cyclononadienyl, cyclodecenyl,cyclodecadienyl and the like. Cycloalkenyl groups can be optionallysubstituted with one or more substituents.

As used herein, the term “heterocycle” or “heterocyclyl” means amonocyclic or polycyclic heterocyclic ring (typically having 3- to14-members) which is either a saturated ring or an unsaturatednon-aromatic ring. A 3-membered heterocycle can contain from 1 to 3heteroatoms, and a 4- to 14-membered heterocycle can contain from 1 toabout 8 heteroatoms. Each heteroatom is independently selected fromnitrogen, which can be quaternized; oxygen; and sulfur, includingsulfoxide and sulfone. The heterocycle may be attached via anyheteroatom or carbon atom. Representative heterocycles includemorpholinyl, thiomorpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl,piperazinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl,tetrahydrofuranyl, tetrahydropyranyl, 4H-pyranyl, tetrahydropyrindinyl,tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, andthe like. A heteroatom may be substituted with a protecting group knownto those of ordinary skill in the art, for example, the hydrogen on anitrogen may be substituted with a tert-butoxycarbonyl group.Furthermore, the heterocyclyl may be optionally substituted with one ormore substituents (including without limitation a halo, an alkyl, ahaloalkyl, or aryl). Only stable isomers of such substitutedheterocyclic groups are contemplated in this definition.

As used herein, the term “heteroaromatic” or “heteroaryl” means amonocyclic or polycyclic heteroaromatic ring (or radical thereof)comprising carbon atom ring members and one or more heteroatom ringmembers (such as, for example, oxygen, sulfur or nitrogen). Typically,the heteroaromatic ring has from 5 to about 14 ring members in which atleast 1 ring member is a heteroatom selected from oxygen, sulfur andnitrogen. In another embodiment, the heteroaromatic ring is a 5 or 6membered ring and may contain from 1 to about 4 heteroatoms. In anotherembodiment, the heteroaromatic ring system has a 7 to 14 ring membersand may contain from 1 to about 7 heteroatoms. Representativeheteroaryls include pyridyl, furyl, thienyl, pyrrolyl, oxazolyl,imidazolyl, indolizinyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl,pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, triazolyl, pyridinyl,thiadiazolyl, pyrazinyl, quinolyl, isoquniolyl, indazolyl, benzoxazolyl,benzofuryl, benzothiazolyl, indolizinyl, imidazopyridinyl, isothiazolyl,tetrazolyl, benzo[1,3]dioxolyl, 2,3-dihydro-benzo[1,4]dioxinyl,benzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl,benzoxadiazolyl, indolyl, tetrahydroindolyl, azaindolyl, imidazopyridyl,qunizaolinyl, purinyl, pyrrolo[2,3]pyrimidyl, pyrazolo[3,4]pyrimidyl orbenzo(b)thienyl and the like. Heteroaryl groups may be optionallysubstituted with one or more substituents

A heteroaralkyl group refers to a heteroaryl group that is attached toanother moiety via an alkylene linker. Heteroaralkyl groups can besubstituted or unsubstituted with one or more substituents.

As used herein, the term “halogen” or “halo” means —F, —Cl, —Br or —I.

As used herein, the term “haloalkyl” means an alkyl group in which oneor more —H is replaced with a halo group. Examples of haloalkyl groupsinclude —CF₃, —CHF₂, —CCl₃, —CH₂CH₂Br, —CH₂CH(CH₂CH₂Br)CH₃, —CHICH₃, andthe like.

As used herein, the term “haloalkoxy” means an alkoxy group in which oneor more —H is replaced with a halo group. Examples of haloalkoxy groupsinclude —OCF₃ and —OCHF₂.

The terms “bioisostere” and “bioisosteric replacement” have the samemeanings as those generally recognized in the art. Bioisosteres areatoms, ions, or molecules in which the peripheral layers of electronscan be considered substantially identical. The term bioisostere isusually used to mean a portion of an overall molecule, as opposed to theentire molecule itself. Bioisosteric replacement involves using onebioisostere to replace another with the expectation of maintaining orslightly modifying the biological activity of the first bioisostere. Thebioisosteres in this case are thus atoms or groups of atoms havingsimilar size, shape and electron density. Preferred bioisosteres ofesters, amides or carboxylic acids are compounds containing two sitesfor hydrogen bond acceptance. In one embodiment, the ester, amide orcarboxylic acid bioisostere is a 5-membered monocyclic heteroaryl ring,such as an optionally substituted 1H-imidazolyl, an optionallysubstituted oxazolyl, 1H-tetrazolyl, [1,2,4]triazolyl, or an optionallysubstituted [1,2,4]oxadiazolyl.

As used herein, the terms “subject”, “patient” and “animal”, are usedinterchangeably and include, but are not limited to, a cow, monkey,horse, sheep, pig, mini pig, chicken, turkey, quail, cat, dog, mouse,rat, rabbit, guinea pig and human. The preferred subject, patient oranimal is a human.

As used herein, the term “lower” refers to a group having up to fourcarbon atoms. For example, a “lower alkyl” refers to an alkyl radicalhaving from 1 to 4 carbon atoms, and a “lower alkenyl” or “loweralkynyl” refers to an alkenyl or alkynyl radical having from 2 to 4carbon atoms, respectively. A lower alkoxy or a lower alkylsulfanylrefers to an alkoxy or an alkylsulfanyl having from 1 to 4 carbon atoms.Lower substituents are typically preferred.

Where a particular substituent, such as an alkyl substituent, occursmultiple times in a given structure or moeity, the identity of thesubstitutent is independent in each case and may be the same as ordifferent from other occurrences of that substituent in the structure ormoiety. Furthermore, individual substituents in the specific embodimentsand exemplary compounds of this invention are preferred in combinationwith other such substituents in the compounds of this invention, even ifsuch individual substituents are not expressly noted as being preferredor not expressly shown in combination with other substituents.

The compounds of the invention are defined herein by their chemicalstructures and/or chemical names. Where a compound is referred to byboth a chemical structure and a chemical name, and the chemicalstructure and chemical name conflict, the chemical structure isdeterminative of the compound's identity.

Suitable substituents for an alkyl, alkoxy, alkylsulfanyl, alkylamino,dialkylamino, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,heterocyclyl, aryl, aralkyl, heteroaryl, and heteroaralkyl groupsinclude any substituent which will form a stable compound of theinvention. Examples of substituents for an alkyl, alkoxy, alkylsulfanyl,alkylamino, dialkylamino, alkylene, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, heterocyclyl, aryl, aralkyl, heteroaryl, and heteroaralkylinclude an alkyl, an alkoxy, an alkylsulfanyl, an alkylamino, adialkylamino, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aheterocyclyl, an aryl, a heteroaryl, an aralkyl, a heteraralkyl, ahaloalkyl, —C(O)NR₃₄R₃₅, —NR₃₆C(O)R₃₇, halo, —OR₃₆, cyano, nitro,haloalkoxy, —C(O)R₃₆, —NR₃₄R₃₅, —SR₃₆, —C(O)OR₃₆, —OC(O)R₃₆,—NR₃₆C(O)NR₃₄R₃₅, —OC(O)NR₃₄R₃₅, —NR₃₆C(O)OR₃₇, —S(O)_(p)R₃₆, or—S(O)_(p)NR₃₄R₃₅, wherein R₃₄ and R₃₅, for each occurrence are,independently, H, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, acycloalkenyl, a heterocyclyl, an aryl, a heteroaryl, an aralkyl, or aheteraralkyl; or R₃₄ and R₃₅ taken together with the nitrogen to whichthey are attached is a heterocyclyl or a heteroaryl; and R₃₆ and R₃₇ foreach occurrence are, independently, H, an alkyl, an alkenyl, an alkynyl,a cycloalkyl, a cycloalkenyl, a heterocyclyl, an aryl, a heteroaryl, anaralkyl, or a heteraralkyl;

In addition, alkyl, cycloalkyl, alkylene, a heterocyclyl, and anysaturated portion of a alkenyl, cycloalkenyl, alkynyl, aralkyl, andheteroaralkyl groups, may also be substituted with ═O, ═S, ═N—R₃₂.

When a heterocyclyl, heteroaryl, or heteroaralkyl group contains anitrogen atom, it may be substituted or unsubstituted. When a nitrogenatom in the aromatic ring of a heteroaryl group has a substituent thenitrogen may be a quaternary nitrogen.

Choices and combinations of substituents and variables envisioned bythis invention are only those that result in the formation of stablecompounds. The term “stable”, as used herein, refers to compounds whichpossess stability sufficient to allow manufacture and which maintainsthe integrity of the compound for a sufficient period of time to beuseful for the purposes detailed herein (e.g., therapeutic orprophylactic administration to a subject). Typically, such compounds arestable at a temperature of 40° C. or less, in the absence of excessivemoisture, for at least one week. Such choices and combinations will beapparent to those of ordinary skill in the art and may be determinedwithout undue experimentation.

Unless indicated otherwise, the compounds of the invention containingreactive functional groups (such as, without limitation, carboxy,hydroxy, and amino moieties) also include protected derivatives thereof.“Protected derivatives” are those compounds in which a reactive site orsites are blocked with one ore more protecting groups. Suitableprotecting groups for carboxy moieties include benzyl, tert-butyl, andthe like. Suitable protecting groups for amino and amido groups includeacetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitableprotecting groups for hydroxy include benzyl, trimethyl silyl (TMS) andthe like. Other suitable protecting groups are well known to those ofordinary skill in the art and include those found in T. W. Greene,Protecting Groups in Organic Synthesis, John Wiley & Sons, Inc. 1981,the entire teachings of which are incorporated herein by reference.

As used herein, the term “compound(s) of this invention” and similarterms refers to a compound of any one of formulas (I) through (X), (IA)through (XA), (IB) through (XB), or of Table 1, or a pharmaceuticallyacceptable salt, solvate, clathrate, or prodrug thereof and also includeprotected derivatives thereof.

As used herein, the term “amino acid residue” refers to what is left ofan amino acid (losing a H⁺ from the nitrogenous side, an OH⁻ from thecarboxylic side, or a H⁺ from the nitrogenous side and an OH⁻ from thecarboxylic side) in the formation of a peptide bond(s). An “amino acidanalog” includes D or L amino acids having the following formula:NH₂—CHR—C(O)OH, wherein R is an optionally substituted alkyl group, anoptionally substituted heteroalkyl group, an optionally substitutedaromatic group, or an optionally substituted heteroaromatic group, andwherein R does not correspond to the side chain of a naturally-occurringamino acid. An “amino acid residue analog” refers to what is left of anamino acid analog (losing a H⁺ from the nitrogenous side, an OH⁻ fromthe carboxylic side, or a H⁺ from the nitrogenous side and an OH^(—)from the carboxylic side) in the formation of a peptide bond(s).

As used herein and unless otherwise indicated, the term “prodrug” meansa derivative of a compound that can hydrolyze, oxidize, or otherwisereact under biological conditions (in vitro or in vivo) to provide acompound of this invention. Prodrugs may only become active upon suchreaction under biological conditions, but they may have activity intheir unreacted forms. Examples of prodrugs contemplated in thisinvention include, but are not limited to, analogs or derivatives ofcompounds of any one of formulas (I) through (X), (IA) through (XA),(IB) through (XB), or of Table 1 that comprise biohydrolyzable moietiessuch as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzablecarbamates, biohydrolyzable carbonates, biohydrolyzable ureides, andbiohydrolyzable phosphate analogues. Other examples of prodrugs includederivatives of compounds of any one of formulas (I) through (X), (IA)through (XA), (IB) through (XB), or of Table 1 that comprise —NO, —NO₂,—ONO, or —ONO₂ moieties. Prodrugs can typically be prepared usingwell-known methods, such as those described by 1 BURGER'S MEDICINALCHEMISTRY AND DRUG DISCOVERY (1995) 172-178, 949-982 (Manfred E. Wolffed., 5^(th) ed), the entire teachings of which are incorporated hereinby reference.

As used herein and unless otherwise indicated, the terms“biohydrolyzable amide”, “biohydrolyzable ester”, “biohydrolyzablecarbamate”, “biohydrolyzable carbonate”, “biohydrolyzable ureide” and“biohydrolyzable phosphate analogue” mean an amide, ester, carbamate,carbonate, ureide, or phosphate analogue, respectively, that either: 1)does not destroy the biological activity of the compound and confersupon that compound advantageous properties in vivo, such as uptake,duration of action, or onset of action; or 2) is itself biologicallyinactive but is converted in vivo to a biologically active compound.Examples of biohydrolyzable amides include, but are not limited to,lower alkyl amides, α-amino acid amides, alkoxyacyl amides, andalkylaminoalkylcarbonyl amides. Examples of biohydrolyzable estersinclude, but are not limited to, lower alkyl esters, alkoxyacyloxyesters, alkyl acylamino alkyl esters, and choline esters. Examples ofbiohydrolyzable carbamates include, but are not limited to, loweralkylamines, substituted ethylenediamines, aminoacids,hydroxyalkylamines, heterocyclic and heteroaromatic amines, andpolyether amines.

As used herein, the term “pharmaceutically acceptable salt,” is a saltformed from an acid and a basic group of one of the compounds of any oneof formulas (I) through (X), (IA) through (XA), (IB) through (XB), or ofTable 1. Illustrative salts include, but are not limited, to sulfate,citrate, acetate, oxalate, chloride, bromide, iodide, nitrate,bisulfate, phosphate, acid phosphate, isonicotinate, lactate,salicylate, acid citrate, tartrate, oleate, tannate, pantothenate,bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate,gluconate, glucaronate, saccharate, formate, benzoate, glutamate,methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate,and pamoate (i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts.The term “pharmaceutically acceptable salt” also refers to a saltprepared from a compound of any one of formulas (I) through (X), (IA)through (XA), (IB) through (XB), or of Table 1 having an acidicfunctional group, such as a carboxylic acid functional group, and apharmaceutically acceptable inorganic or organic base. Suitable basesinclude, but are not limited to, hydroxides of alkali metals such assodium, potassium, and lithium; hydroxides of alkaline earth metal suchas calcium and magnesium; hydroxides of other metals, such as aluminumand zinc; ammonia, and organic amines, such as unsubstituted orhydroxy-substituted mono-, di-, or trialkylamines; dicyclohexylamine;tributyl amine; pyridine; N-methyl,N-ethylamine; diethylamine;triethylamine; mono-, bis-, or tris-(2-hydroxy-lower alkyl amines), suchas mono-, bis-, or tris-(2-hydroxyethyl)-amine,2-hydroxy-tert-butylamine, or tris-(hydroxymethyl)methylamine,N,N,-di-lower alkyl-N-(hydroxy lower alkyl)-amines, such asN,N-dimethyl-N-(2-hydroxyethyl)-amine, or tri-(2-hydroxyethyl)amine;N-methyl-D-glucamine; and amino acids such as arginine, lysine, and thelike. The term “pharmaceutically acceptable salt” also refers to a saltprepared from a compound of any one of formulas (I) through (X), (IA)through (XA), (IB) through (XB), or of Table 1 having a basic functionalgroup, such as an amino functional group, and a pharmaceuticallyacceptable inorganic or organic acid. Suitable acids include, but arenot limited to, hydrogen sulfate, citric acid, acetic acid, oxalic acid,hydrochloric acid, hydrogen bromide, hydrogen iodide, nitric acid,phosphoric acid, isonicotinic acid, lactic acid, salicylic acid,tartaric acid, ascorbic acid, succinic acid, maleic acid, besylic acid,fumaric acid, gluconic acid, glucaronic acid, saccharic acid, formicacid, benzoic acid, glutamic acid, methanesulfonic acid, ethanesulfonicacid, benzenesulfonic acid, and p-toluenesulfonic acid.

As used herein, the term “pharmaceutically acceptable solvate,” is asolvate formed from the association of one or more solvent molecules toone or more molecules of a compound of any one of formulas (I) through(X), (IA) through (XA), (IB) through (XB), or of Table 1. The termsolvate includes hydrates (e.g., hemi-hydrate, mono-hydrate, dihydrate,trihydrate, tetrahydrate, and the like).

As used herein, the term “clathrate” means a compound of the presentinvention or a salt thereof in the form of a crystal lattice thatcontains spaces (e.g., channels) that have a guest molecule (e.g., asolvent or water) trapped within.

Inhibition of tubulin polymerization can be determined by any methodknown to those skilled in the art, such as the method described hereinin Example 7. In addition the amount of a tubulin polymerizationinhibitor that inhibits 50% of tubulin polymerization that occurs in theabsence of the inhibitor (i.e., the IC₅₀) can be determined bypre-incubating purified tubulin with various amounts of an inhibitor for15 minutes at 37° C. The mixture is then cooled to room temperature andGTP is added to induce tubulin polymerization. The polymerization can bemonitored in a spectrophotometer at 350 nm. A typical reaction mixtures(0.25 mL) contains 1.5 mg/mL tubulin, 0.6 mg/mL microtubule-associatedproteins (MAPs), 0.5 mM GTP, 0.5 mIM MgCl.sub.2, 4% DMSO and 0.1M4-morpholineethanesulfonate buffer (MES, pH 6.4).

As used herein, a “proliferative disorder” or a “hyperproliferativedisorder,” and other equivalent terms, means a disease or medicalcondition involving pathological growth of cells. Proliferativedisorders include cancer, smooth muscle cell proliferation, systemicsclerosis, cirrhosis of the liver, adult respiratory distress syndrome,idiopathic cardiomyopathy, lupus erythematosus, retinopathy (e.g.,diabetic retinopathy or other retinopathies), choroidalneovascularisation (e.g., macular degeneration), cardiac hyperplasia,reproductive system associated disorders such as benign prostatichyperplasia and ovarian cysts, pulmonary fibrosis, endometriosis,fibromatosis, harmatomas, lymphangiomatosis, sarcoidosis, and desmoidtumors.

Smooth muscle cell proliferation includes hyperproliferation of cells inthe vasculature, for example, intimal smooth muscle cell hyperplasia,restenosis and vascular occlusion, particularly stenosis followingbiologically- or mechanically-mediated vascular injury, e.g., vascularinjury associated with angioplasty. Moreover, intimal smooth muscle cellhyperplasia can include hyperplasia in smooth muscle other than thevasculature, e.g., bile duct blockage, bronchial airways of the lung inpatients with asthma, in the kidneys of patients with renal interstitialfibrosis, and the like.

Non-cancerous proliferative disorders also include hyperproliferation ofcells in the skin such as psoriasis and its varied clinical forms,Reiter's syndrome, pityriasis rubra pilaris, and hyperproliferativevariants of disorders of keratinization (e.g., actinic keratosis, senilekeratosis), scleroderma, and the like.

In a preferred embodiment, the proliferative disorder is cancer. Cancersthat can be treated or prevented by the methods of the present inventioninclude, but are not limited to human sarcomas and carcinomas, e.g.,fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenicsarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma,lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor,leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer,breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma,basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceousgland carcinoma, papillary carcinoma, papillary adenocarcinomas,cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renalcell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma,seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testiculartumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma,epithelial carcinoma, glioma, astrocytoma, medulloblastoma,craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acousticneuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma,retinoblastoma; leukemias, e.g., acute lymphocytic leukemia and acutemyelocytic leukemia (myeloblastic, promyelocytic, myelomonocytic,monocytic and erythroleukemia); chronic leukemia (chronic myelocytic(granulocytic) leukemia and chronic lymphocytic leukemia); andpolycythemia vera, lymphoma (Hodgkin's disease and non-Hodgkin'sdisease), multiple myeloma, Waldenstrobm's macroglobulinemia, and heavychain disease.

Other examples of leukemias include acute and/or chronic leukemias,e.g., lymphocytic leukemia (e.g., as exemplified by the p388 (murine)cell line), large granular lymphocytic leukemia, and lymphoblasticleukemia; T-cell leukemias, e.g., T-cell leukemia (e.g., as exemplifiedby the CEM, Jurkat, and HSB-2 (acute), YAC-1(murine) cell lines),T-lymphocytic leukemia, and T-lymphoblastic leukemia; B cell leukemia(e.g., as exemplified by the SB (acute) cell line), and B-lymphocyticleukemia; mixed cell leukemias, e.g., B and T cell leukemia and B and Tlymphocytic leukemia; myeloid leukemias, e.g., granulocytic leukemia,myelocytic leukemia (e.g., as exemplified by the HL-60 (promyelocyte)cell line), and myelogenous leukemia (e.g., as exemplified by theK562(chronic)cell line); neutrophilic leukemia; eosinophilic leukemia;monocytic leukemia (e.g., as exemplified by the THP-1(acute) cell line);myelomonocytic leukemia; Naegeli-type myeloid leukemia; andnonlymphocytic leukemia. Other examples of leukemias are described inChapter 60 of The Chemotherapy Sourcebook, Michael C. Perry Ed.,Williams & Williams (1992) and Section 36 of Holland Frie CancerMedicine 5th Ed., Bast et al. Eds., B.C. Decker Inc. (2000). The entireteachings of the preceding references are incorporated herein byreference.

In one embodiment, the compounds of the invention are believed to beparticularly effective in treating subject with hematologicalmalignancies (e.g., Hodgkin's disease, Non-Hodgkin lymphoma, acutelymphoblastic leukemia, acute myelogenous leukemia, chronic myelogenousleukemia, chronic lymphocytic leukemia, and multiple myeloma). Inanother embodiment, the compounds of the invention are believed to beparticularly useful in treating solid tumors.

In one embodiment, the compounds of the invention are particularlyeffective at treating subjects whose cancer has become “multi-drugresistant”. A cancer which initially responded to an anti-cancer drugbecomes resistant to the anti-cancer drug when the anti-cancer drug isno longer effective in treating the subject with the cancer. Forexample, many tumors will initially respond to treatment with ananti-cancer drug by decreasing in size or even going into remission,only to develop resistance to the drug. Drug resistant tumors arecharacterized by a resumption of their growth and/or reappearance afterhaving seemingly gone into remission, despite the administration ofincreased dosages of the anti-cancer drug. Cancers that have developedresistance to two or more anti-cancer drugs are said to be “multi-drugresistant”. For example, it is common for cancers to become resistant tothree or more anti-cancer agents, often five or more anti-cancer agentsand at times ten or more anti-cancer agents.

An “effective amount” is the quantity of compound in which a beneficialoutcome is achieved when the compound is administered to a subject oralternatively, the quantity of compound that possess a desired activityin vivo or in vitro. In the case of proliferative disorders, abeneficial clinical outcome includes reduction in the extent or severityof the symptoms associated with the disease or disorder and/or anincrease in the longevity and/or quality of life of the subject comparedwith the absence of the treatment. For example, for a subject withcancer, a “beneficial clinical outcome” includes a reduction in tumormass, a reduction in the rate of tumor growth, a reduction inmetastasis, a reduction in the severity of the symptoms associated withthe cancer and/or an increase in the longevity of the subject comparedwith the absence of the treatment. The precise amount of compoundadministered to a subject will depend on the type and severity of thedisease or condition and on the characteristics of the subject, such asgeneral health, age, sex, body weight and tolerance to drugs. It willalso depend on the degree, severity and type of proliferative disorder.The skilled artisan will be able to determine appropriate dosagesdepending on these and other factors. Effective amounts of the disclosedcompounds typically range between about 1 mg/mm² per day and about 10grams/mm² per day, and preferably between 10 m g/mm² per day and about 1gram/mm².

In one embodiment, compounds of the invention are vascular targetingagents. In one aspect, compounds of the invention are effective forblocking, occluding, or otherwise disrupting blood flow in“neovasculature.” In one aspect, the invention provides a noveltreatment for diseases involving the growth of new blood vessels(“neovasculature”), including, but not limited to: cancer; infectiousdiseases; autoimmune disorders; benign tumors, e.g. hemangiomas,acoustic neuromas, neurofibromas, trachomas, and pyogenic granulomas;artheroscleric plaques; ocular angiogenic diseases, e.g., diabeticretinopathy, retinopathy of prematurity, macular degeneration, cornealgraft rejection, neovascular glaucoma, retrolental fibroplasia,rubeosis, retinoblastoma, persistent hyperplastic vitreous syndrome,choroidal neovascularization, uvietis and Pterygia (abnormal bloodvessel growth) of the eye; rheumatoid arthritis; psoriasis; warts;allergic dermatitis; blistering disease; Karposi sarcoma; delayed woundhealing; endometriosis; uterine bleeding; ovarian cysts; ovarianhyperstimulation; vasculogenesis; granulations; hypertrophic scars(keloids); nonunion fractures; scleroderma; trachoma; vascularadhesions; vascular malformations; DiGeorge syndrome; HHT; transplantarteriopathy; restinosis; obesity; myocardial angiogenesis; coronarycollaterals; cerebral collaterals; arteriovenous malformations; ischemiclimb angiogenesis; primary pulmonary hypertension; asthma; nasal polyps;inflammatory bowel disease; periodontal disease; ascites; peritonealadhesions; Osler-Webber Syndrome; plaque neovascularization;telangiectasia; hemophiliac joints; synovitis; osteomyelitis; osteophyteformation; angiofibroma; fibromuscular dysplasia; wound granulation;Crohn's disease; and atherosclerosis.

Vascular targeting can be demonstrated by any method known to thoseskilled in the art, such as the method described herein in Example 11.

The compounds of the invention may contain one or more chiral centersand/or double bonds and, therefore, may exist as stereoisomers, such asdouble-bond isomers (i.e., geometric isomers), enantiomers, ordiastereomers. According to this invention, the chemical structuresdepicted herein, including the compounds of this invention, encompassall of the corresponding compounds' enantiomers and stereoisomers, thatis, both the stereomerically pure form (e.g., geometrically pure,enantiomerically pure, or diastereomerically pure) and enantiomeric,diastereomeric, and geometric isomeric mixtures. In some cases, oneenantiomer, diastereomer, or geometric isomer will possess superioractivity or an improved toxicity or kinetic profile compared to others.In those cases, such enantiomers, diastereomers, and geometric isomersof a compound of this invention are preferred.

As used herein, a composition that “substantially” comprises a compoundmeans that the composition contains more than about 80% by weight, morepreferably more than about 90% by weight, even more preferably more thanabout 95% by weight, and most preferably more than about 97% by weightof the compound.

As used herein, a composition that is “substantially free” of a compoundmeans that the composition contains less than about 20% by weight, morepreferably less than about 10% by weight, even more preferably less thanabout 5% by weight, and most preferably less than about 3% by weight ofthe compound.

As used herein, a reaction that is “substantially complete” means thatthe reaction contains more than about 80% by weight of the desiredproduct, more preferably more than about 90% by weight of the desiredproduct, even more preferably more than about 95% by weight of thedesired product, and most preferably more than about 97% by weight ofthe desired product.

As used herein, a racemic mixture means about 50% of one enantiomer andabout 50% of is corresponding enantiomer relative to all chiral centersin the molecule. The invention encompasses all enantiomerically-pure,enantiomerically-enriched, diastereomerically pure, diastereomericallyenriched, and racemic mixtures of the compounds of any one of formulas(I) through (X), (IA) through (XA), (IB) through (XB), or of Table 1.

Enantiomeric and diastereomeric mixtures can be resolved into theircomponent enantiomers or stereoisomers by well known methods, such aschiral-phase gas chromatography, chiral-phase high performance liquidchromatography, crystallizing the compound as a chiral salt complex, orcrystallizing the compound in a chiral solvent. Enantiomers anddiastereomers can also be obtained from diastereomerically- orenantiomerically-pure intermediates, reagents, and catalysts by wellknown asymmetric synthetic methods.

When administered to a patient, e.g., to a non-human animal forveterinary use or for improvement of livestock, or to a human forclinical use, the compounds of the invention are typically administeredin isolated form or as the isolated form in a pharmaceuticalcomposition. As used herein, “isolated” means that the compounds of theinvention are separated from other components of either (a) a naturalsource, such as a plant or cell, preferably bacterial culture, or (b) asynthetic organic chemical reaction mixture. Preferably, viaconventional techniques, the compounds of the invention are purified. Asused herein, “purified” means that when isolated, the isolate containsat least 95%, preferably at least 98%, of a single compound of theinvention by weight of the isolate.

Only those choices and combinations of substituents that result in astable structure are contemplated. Such choices and combinations will beapparent to those of ordinary skill in the art and may be determinedwithout undue experimentation.

The invention can be understood more fully by reference to the followingdetailed description and illustrative examples, which are intended toexemplify non-limiting embodiments of the invention.

SPECIFIC EMBODIMENTS

The invention relates to compounds and pharmaceutical compositions thatare useful for inhibiting tubulin polymerization and are particularlyuseful in treating or preventing proliferative disorders, such ascancer. The invention also relates to compounds and pharmaceuticalcompositions that are useful as vascular targeting agents, particularly,in blocking, occluding, or otherwise disrupting blood flow inneovasculature.

In one embodiment, the invention relates to compounds of formula (I):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein:

one of R_(a) or R_(b) is —H and the other is an optionally substitutedaryl, or an optionally substituted heteroaryl; and

R₂ is an optionally substituted phenyl, an optionally substituted2,3-dihydro-benzo[1,4]dioxinyl, an optionally substitutedbenzo[1,3]dioxolyl, an optionally substituted biphenyl, an optionallysubstituted 4-pyridinyl-phenyl, an optionally substituted quinolinyl, anoptionally substituted isoquinolinyl, an optionally substituted1H-indolyl, an optionally substituted pyridinyl, an optionallysubstituted oxazolyl, an optionally substituted isoxazolyl, anoptionally substituted thiazolyl, an optionally substitutedisothiazolyl, an optionally substituted imidazolyl, an optionallysubstituted pyrrolyl, an optionally substituted pyrazolyl, an optionallysubstituted furanyl, an optionally substituted thiophenyl, an optionallysubstituted thiadiazolyl, an optionally substituted oxadiazolyl, anoptionally substituted chromanyl, an optionally substitutedisochromanyl, an optionally substituted pyridazinyl, an optionallysubstituted pyrimidinyl, an optionally substituted pyrazinyl, anoptionally substituted benzothiophenyl, an optionally substituted2,3-dihydro-benzothiophenyl, an optionally substituted benzofuranyl, anoptionally substituted 2,3-dihydro-benzofuranyl, an optionallysubstituted 1H-benzoimidazolyl, an optionally substitutedbenzothiazolyl, an optionally substituted benzooxazolyl, an optionallysubstituted 1H-benzotriazolyl, an optionally substituted 1H-indazolyl,an optionally substituted 9H-purinyl, an optionally substitutedpyrrolopyrimidinyl, an optionally substituted pyrrolopyrazinyl, anoptionally substituted pyrrolopyridazinyl, an optionally substitutedimidazopyrazinyl, or an optionally substituted imidazolpyridazinyl.

In another embodiment, the invention relates to compounds of formula(II):

or a pharmaceutically acceptable salt, solvate, clathrate, and prodrugthereof, wherein:

one of R_(c) or R_(d) is —H and the other is an optionally substitutedheteroaryl, an unsubstituted phenyl, or a substituted phenyl representedby one of the following formulas:

R₄ is an optionally substituted aryl or an optionally substitutedheteroaryl;

R₁₈, R₁₉, R₂₂, and R₂₃, are each, independently, halo, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, an optionally substituted heteraralkyl,cyano, nitro, guanadino, a haloalkyl, a haloalkoxy, a heteroalkyl, —OR₇,—NR₁₀R₁₁, —C(O)R₇, C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—OP(O)(OR₇)₂, —SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇,—S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁;

R₂₀ is an optionally substituted alkyl, an optionally substitutedalkenyl, an optionally substituted alkynyl, an optionally substitutedcycloalkyl, an optionally substituted cycloalkenyl, an optionallysubstituted heterocyclyl, an optionally substituted aryl, an optionallysubstituted heteroaryl, an optionally substituted aralkyl, an optionallysubstituted heteraralkyl, cyano, nitro, guanadino, a haloalkyl, ahaloalkoxy, a heteroalkyl, —OR₁₇, —NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇,—C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂, —SR(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇,—OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁;

R₂₁ is halo, an optionally substituted alkyl, an optionally substitutedalkenyl, an optionally substituted alkynyl, an optionally substitutedcycloalkyl, an optionally substituted cycloalkenyl, an optionallysubstituted heterocyclyl, an optionally substituted aryl, an optionallysubstituted heteroaryl, an optionally substituted aralkyl, an optionallysubstituted heteraralkyl, cyano, nitro, guanadino, a haloalkyl, ahaloalkoxy, a heteroalkyl, —OR₁₇, —NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇,—C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂, SR(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇,—OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁;

R₇ and R₈, for each occurrence, are, independently, —H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, or an optionally substitutedheteraralkyl;

R₁₀ and R₁₁, for each occurrence, are independently —H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, or an optionally substitutedheteraralkyl; or R₁₀ and R₁₁, taken together with the nitrogen to whichthey are attached, form an optionally substituted heterocyclyl or anoptionally substituted heteroaryl;

R₁₇, for each occurrence, is independently, an optionally substitutedalkyl, an optionally substituted alkenyl, an optionally substitutedalkynyl, an optionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl; and

p is 1 or 2.

In another embodiment, the invention relates to compounds of formula(III):

or a pharmaceutically acceptable salt, solvate, clathrate, and prodrugthereof, wherein:

one of R_(e) or R_(f) is —H and the other is an optionally substitutedaryl or an optionally substituted heteroaryl selected from the groupconsisting of an optionally substituted 2,3-dihydro-benzo[1,4]dioxinyl,an optionally substituted benzo[1,3]dioxolyl, an optionally substitutedquinolinyl, an optionally substituted isoquinolinyl, an optionallysubstituted 1H-indolyl, an optionally substituted pyridinyl, anoptionally substituted oxazolyl, an optionally substituted isoxazolyl,an optionally substituted thiazolyl, an optionally substitutedisothiazolyl, an optionally substituted imidazolyl, an optionallysubstituted pyrazolyl, an optionally substituted furanyl, an optionallysubstituted thiophenyl, an optionally substituted thiadiazolyl, anoptionally substituted oxadiazolyl, an optionally substituted chromanyl,an optionally substituted isochromanyl, an optionally substitutedpyridazinyl, an optionally substituted pyrimidinyl, an optionallysubstituted pyrazinyl, an optionally substituted benzothiophenyl, anoptionally substituted 2,3-dihydro-benzothiophenyl, an optionallysubstituted benzofuranyl, an optionally substituted2,3-dihydro-benzofuranyl, an optionally substituted 1H-benzoimidazolyl,an optionally substituted benzothiazolyl, an optionally substitutedbenzooxazolyl, an optionally substituted 1H-benzotriazolyl, anoptionally substituted 1H-indazolyl, an optionally substituted9H-purinyl, an optionally substituted pyrrolopyrimidinyl, an optionallysubstituted pyrrolopyrazinyl, an optionally substitutedpyrrolopyridazinyl, an optionally substituted imidazopyrazinyl, or anoptionally substituted imidazolpyridazinyl; and

R₂ is defined as for formula (I).

In another embodiment, the invention relates to compounds of formula(IV):

or a pharmaceutically acceptable salt, solvate, clathrate, and prodrugthereof, wherein:

one of R_(g) or R_(h) is —H and the other is:

-   -   i) an unsubstituted phenyl or a substituted phenyl represented        by one of the following formulas:

-   -    or    -   ii) an optionally substituted heteroaryl selected from the group        consisting of an optionally substituted        2,3-dihydro-benzo[1,4]dioxinyl, an optionally substituted        benzo[1,3]dioxolyl, an optionally substituted quinolinyl, an        optionally substituted isoquinolinyl, an optionally substituted        1H-indolyl, an optionally substituted pyridinyl, an optionally        substituted oxazolyl, an optionally substituted isoxazolyl, an        optionally substituted thiazolyl, an optionally substituted        isothiazolyl, an optionally substituted imidazolyl, an        optionally substituted pyrazolyl, an optionally substituted        furanyl, an optionally substituted thiophenyl, an optionally        substituted thiadiazolyl, an optionally substituted oxadiazolyl,        an optionally substituted chromanyl, an optionally substituted        isochromanyl, an optionally substituted pyridazinyl, an        optionally substituted pyrimidinyl, an optionally substituted        pyrazinyl, an optionally substituted benzothiophenyl, an        optionally substituted 2,3-dihydro-benzothiophenyl, an        optionally substituted benzofuranyl, an optionally substituted        2,3-dihydro-benzofuranyl, an optionally substituted        1H-benzoimidazolyl, an optionally substituted benzothiazolyl, an        optionally substituted benzooxazolyl, an optionally substituted        1H-benzotriazolyl, an optionally substituted 1H-indazolyl, an        optionally substituted 9H-purinyl, an optionally substituted        pyrrolopyrimidinyl, an optionally substituted pyrrolopyrazinyl,        an optionally substituted pyrrolopyridazinyl, an optionally        substituted imidazopyrazinyl, or an optionally substituted        imidazolpyridazinyl; and

R₄, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃ are defined as for formula (II).

In another embodiment, the invention relates to compounds of formula(V):

and pharmaceutically acceptable salts, solvates, clathrates, or prodrugsthereof, wherein:

one of R_(i) or R_(j) is —H and the other is represented by thefollowing formula:

X₁ and X₂ are each, independently, CH or N;

R₁₂, R₁₃ and R₁₄ are each, independently, halo, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, an optionally substituted heteraralkyl,cyano, nitro, guanadino, a haloalkyl, a haloalkoxy, a heteroalkyl, —OR₇,—NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—OR(O)(OR₇)₂, —SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇,—S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁;

R₂ is defined as for formula (I); and

R₇, R₈, R₁₀, R₁₁, and p are defined as for formula (II).

In another embodiment, the invention relates to compounds of formula(VI):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein:

one of R_(k) or R_(l) is —H and the other is represented by thefollowing formula:

the dashed line indicates that the bond is a single bond or a doublebond;

X₃ and X₄ are each, independently, CH, N, CH₂, NR₁₆, O, or S;

X₅ and X₆ are each, independently, CR₂₉ or N;

R₁₅ is H, halo, an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, anoptionally substituted heteraralkyl, cyano, nitro, guanadino, ahaloalkyl, a haloalkoxy, a heteroalkyl, —OR₁₇, —NR₁₀R₁₁, —C(O)R₇,—C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂,—SR(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁;

R₁₆ is H, an alkyl, a cycloalkyl, an aralkyl, —C(O)R, wherein R is analkyl, a cycloalkyl, or an aralkyl;

R₂₉, for each occurrence, is independently, H or a substituent; and

R₇, R₈, R₁₀, R₁₁, R₁₇, and p are defined as for formula (II).

In another embodiment, the invention relates to compounds of formula(VII):

and pharmaceutically acceptable salts, solvates, clathrates, or prodrugsthereof, wherein:

one of R_(m) or R_(n) is —H and the other is represented by thefollowing formula:

R₄, R₁₈, R₁₉, and R₂₀ are defined as for formula (II); and

X₁ and X₂ are defined as for formula (V).

In another embodiment, the invention relates to compounds of formula(VIII):

and pharmaceutically acceptable salts, solvates, clathrates, or prodrugsthereof, wherein:

one of Ro or Rp is —H and the other is represented by the followingformula:

R₄, R₂₁, R₂₂, and R₂₃ are defined as for formula (II); and

X₁ and X₂ are defined as for formula (V).

In another embodiment, the invention relates to compounds of formula(IX):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein:

one of R_(q) or R_(r) is —H and the other is represented by thefollowing formula:

R₄ is defined as for formula (II); and

R₁₅ and R₂₉ are defined as for formula (VI).

In another embodiment, the invention relates to compounds of formula(X):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein:

one of R_(s) or R_(t) is —H and the other is represented by thefollowing formula:

R₄ is defined as for formula (II); and

R₁₅, R₁₆, and R₂₉ are defined as for formula (VI).

In another embodiment, the invention relates to compounds of formula(IA):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein:

one of R_(a) or R_(b) is —H and the other is an optionally substitutedaryl, or an optionally substituted heteroaryl; and

R^(x) is (R^(aa))_(m), —R^(aa)—C(O)(CH₂)_(n)C(O)OH,—C(O)(CH₂)_(n)C(O)OH, —C(O)YR^(z), —C(O)NH—R^(aa), or—(R^(aa))_(q)C(O)(Y₁);

R^(y) is —H or lower alkyl;

R^(w) is —H, an alkyl, an alkenyl, an alkynyl, cyano, a haloalkyl, analkoxy, a haloalkoxy, a halo, an amino, an alkylamino, a dialkylamino,—OP(O)(OR₇)₂, —SP(O)(OR₇)₂, nitro, an alkyl ester, or hydroxyl;

R₇ is —H, an optionally substituted alkyl, an optionally substitutedalkenyl, an optionally substituted alkynyl, an optionally substitutedcycloalkyl, an optionally substituted cycloalkenyl, an optionallysubstituted heterocyclyl, an optionally substituted aryl, an optionallysubstituted heteroaryl, an optionally substituted aralkyl, or anoptionally substituted heteraralkyl;

R^(aa) is an amino acid residue or an amino acid residue analog;

Y is CH₂, O, or NH;

R^(z) is Alk-NH₂, Alk-C(O)OH, Het, or Y₁;

Alk is an optionally substituted alkylene;

Het is an optionally substituted heteroalkyl;

Y₁ is a water soluble polymer with a molecular weight less than 60,000daltons;

n is 1, 2, 3, or 4;

m is an integer from 1 to 10; and

q is 0 or 1.

In another embodiment, the invention relates to compounds of formula(IIA):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein:

one of R_(c) or R_(d) is —H and the other is an optionally substitutedheteroaryl, an unsubstituted phenyl, a substituted phenyl represented byone of the following formulas:

R₁₈, R₁₉, R₂₂, and R₂₃, are each, independently, halo, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, an optionally substituted heteraralkyl,cyano, nitro, guanadino, a haloalkyl, a haloalkoxy, a heteroalkyl, —OR₇,—NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—OP(O)(OR₇)₂, —SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇,—S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁;

R₂₀ is an optionally substituted alkyl, an optionally substitutedalkenyl, an optionally substituted alkynyl, an optionally substitutedcycloalkyl, an optionally substituted cycloalkenyl, an optionallysubstituted heterocyclyl, an optionally substituted aryl, an optionallysubstituted heteroaryl, an optionally substituted aralkyl, an optionallysubstituted heteraralkyl, cyano, nitro, guanadino, a haloalkyl, ahaloalkoxy, a heteroalkyl, —OR₁₇, —NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇,—C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂, SP(O)(OR₇)₂, —SR₇₅—S(O)_(p)R₇,—OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁;

R₂₁ is halo, an optionally substituted alkyl, an optionally substitutedalkenyl, an optionally substituted alkynyl, an optionally substitutedcycloalkyl, an optionally substituted cycloalkenyl, an optionallysubstituted heterocyclyl, an optionally substituted aryl, an optionallysubstituted heteroaryl, an optionally substituted aralkyl, an optionallysubstituted heteraralkyl, cyano, nitro, guanadino, a haloalkyl, ahaloalkoxy, a heteroalkyl, —OR₁₇, —NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇,—C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂, SP(O)(OR₇)₂, —SR₇₅—S(O)_(p)R₇,—OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁;

R₇ and R₈, for each occurrence, are, independently, —H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, or an optionally substitutedheteraralkyl;

R₁₀ and R₁₁, for each occurrence, are independently —H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, or an optionally substitutedheteraralkyl; or R₁₀ and R₁₁, taken together with the nitrogen to whichthey are attached, form an optionally substituted heterocyclyl or anoptionally substituted heteroaryl;

R₁₇, for each occurrence, is independently, an optionally substitutedalkyl, an optionally substituted alkenyl, an optionally substitutedalkynyl, an optionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl;

p is 1 or 2; and

R^(x), R^(y), and R^(w) are defined as for formula (IA).

In another embodiment, the invention relates to compounds of formula(IIIA):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein:

one of R_(e) or R_(f) is —H and the other is an optionally substitutedaryl or an optionally substituted heteroaryl selected from the groupconsisting of an optionally substituted 2,3-dihydro-benzo[1,4]dioxinyl,an optionally substituted benzo[1,3]dioxolyl, an optionally substitutedquinolinyl, an optionally substituted isoquinolinyl, an optionallysubstituted 1H-indolyl, an optionally substituted pyridinyl, anoptionally substituted oxazolyl, an optionally substituted isoxazolyl,an optionally substituted thiazolyl, an optionally substitutedisothiazolyl, an optionally substituted imidazolyl, an optionallysubstituted pyrazolyl, an optionally substituted furanyl, an optionallysubstituted thiophenyl, an optionally substituted thiadiazolyl, anoptionally substituted oxadiazolyl, an optionally substituted chromanyl,an optionally substituted isochromanyl, an optionally substitutedpyridazinyl, an optionally substituted pyrimidinyl, an optionallysubstituted pyrazinyl, an optionally substituted benzothiophenyl, anoptionally substituted 2,3-dihydro-benzothiophenyl, an optionallysubstituted benzofuranyl, an optionally substituted2,3-dihydro-benzofuranyl, an optionally substituted 1H-benzoimidazolyl,an optionally substituted benzothiazolyl, an optionally substitutedbenzooxazolyl, an optionally substituted 1H-benzotriazolyl, anoptionally substituted 1H-indazolyl, an optionally substituted9H-purinyl, an optionally substituted pyrrolopyrimidinyl, an optionallysubstituted pyrrolopyrazinyl, an optionally substitutedpyrrolopyridazinyl, an optionally substituted imidazopyrazinyl, or anoptionally substituted imidazolpyridazinyl; and R^(x), R^(y), and R^(w)are defined as for formula (IA).

In another embodiment, the invention relates to compounds of formula(IVA):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein:

one of R_(g) or R_(h) is —H and the other is:

-   -   i) an unsubstituted phenyl or a substituted phenyl represented        by one of the following formulas:

-   -    or    -   ii) an optionally substituted heteroaryl selected from the group        consisting of an optionally substituted        2,3-dihydro-benzo[1,4]dioxinyl, an optionally substituted        benzo[1,3]dioxolyl, an optionally substituted quinolinyl, an        optionally substituted isoquinolinyl, an optionally substituted        1H-indolyl, an optionally substituted pyridinyl, an optionally        substituted oxazolyl, an optionally substituted isoxazolyl, an        optionally substituted thiazolyl, an optionally substituted        isothiazolyl, an optionally substituted imidazolyl, an        optionally substituted pyrazolyl, an optionally substituted        furanyl, an optionally substituted thiophenyl, an optionally        substituted thiadiazolyl, an optionally substituted oxadiazolyl,        an optionally substituted chromanyl, an optionally substituted        isochromanyl, an optionally substituted pyridazinyl, an        optionally substituted pyrimidinyl, an optionally substituted        pyrazinyl, an optionally substituted benzothiophenyl, an        optionally substituted 2,3-dihydro-benzothiophenyl, an        optionally substituted benzofuranyl, an optionally substituted        2,3-dihydro-benzofuranyl, an optionally substituted        1H-benzoimidazolyl, an optionally substituted benzothiazolyl, an        optionally substituted benzooxazolyl, an optionally substituted        1H-benzotriazolyl, an optionally substituted 1H-indazolyl, an        optionally substituted 9H-purinyl, an optionally substituted        pyrrolopyrimidinyl, an optionally substituted pyrrolopyrazinyl,        an optionally substituted pyrrolopyridazinyl, an optionally        substituted imidazopyrazinyl, or an optionally substituted        imidazolpyridazinyl; and

R₇ and R₈, for each occurrence, are, independently, —H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, or an optionally substitutedheteraralkyl;

R₁₀ and R₁₁, for each occurrence, are independently —H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, or an optionally substitutedheteraralkyl; or R₁₀ and R₁₁, taken together with the nitrogen to whichthey are attached, form an optionally substituted heterocyclyl or anoptionally substituted heteroaryl;

R₁₈, R₁₉, R₂₂, and R₂₃, are defined as for formula (IIA);

p is 1 or 2; and

R^(x), R^(y), and R^(w) are defined as for formula (IA).

In another embodiment, the invention relates to compounds of formula(VA):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein:

one of R_(i) or R_(j) is —H and the other is represented by thefollowing formula:

X₁ and X₂ are each, independently, CH or N;

R₁₂, R₁₃ and R₁₄ are each, independently, halo, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, an optionally substituted heteraralkyl,cyano, nitro, guanadino, a haloalkyl, a haloalkoxy, a heteroalkyl, —OR₇,—NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—OP(O)(OR₇)₂, —SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇,—S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₃R₁₁;

R₇, R₈, R₁₀, R₁₁, and p are defined as for formula (IIA); and

R^(x), R^(y), and R^(w) are defined as for formula (IA).

In another embodiment, this invention relates to compounds of formula(VIA):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein:

one of R_(k) or R_(I) is —H and the other is represented by thefollowing formula:

the dashed line indicates that the bond is a single bond or a doublebond;

X₃ and X₄ are each, independently, CH, N, CH₂, NR₁₈, O, or S;

X₅ and X₆ are each, independently, CR₂₉ or N;

R₁₅ is H, halo, an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, anoptionally substituted heteraralkyl, cyano, nitro, guanadino, ahaloalkyl, a haloalkoxy, a heteroalkyl, —OR₁₇, —NR₁₀R₁₁, —C(O)R₇,—C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂, SP(O)(OR₇)₂,—SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or—S(O)_(p)NR₁₀R₁₁;

R₁₆ is H, an alkyl, a cycloalkyl, an aralkyl, —C(O)R, wherein R is analkyl, a cycloalkyl, or an aralkyl;

R₂₉, for each occurrence, is independently, H or a substituent

R₇, R₈, R₁₀, R₁₁, R₁₇, and p are defined as for formula (IIA); and

R^(x), R^(y), and R^(w) are defined as for formula (IA).

In another embodiment, the invention relates to compounds of formula(VIIA):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof,

wherein:

one of R_(m) or R_(n) is —H and the other is represented by thefollowing formula:

X₁ and X₂ are each, independently, CH or N;

R₁₈, R₁₉, and R₂₀ are defined as for formula (IIA); and

R^(x), R^(y), and R^(w) are defined as for formula (IA).

In another embodiment, the invention relates to compounds of formula(VIIIA):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein:

one of R_(o) or R_(p) is —H and the other is represented by thefollowing formula:

X₁ and X₂ are each, independently, CH or N;

R₂₁, R₂₂, and R₂₃ are defined as for formula (IIA); and

R^(x), R^(y), and R^(w) are defined as for formula (IA).

In another embodiment, the invention relates to compounds of formula(IXA):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein:

one of R_(q) or R_(r) is —H and the other is represented by thefollowing formula:

R₁₅ and R₁₉ are defined as for formula (VIA); and

R^(x), R^(y), and R^(w) are defined as for formula (IA).

In another embodiment, the invention relates to compounds of formula(XA):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein:

one of R_(s) or R_(t) is —H and the other is represented by thefollowing formula:

R₁₅, R₁₆, and R₂₉ are defined as for formula (VIA); and

R^(x), R^(y), and R^(w) are defined as for formula (IA).

In another embodiment, the invention relates to compounds of formula(IB):

or a pharmaceutically acceptable salt, solvate, or clathrate, thereof,wherein:

R^(w) is —H, an alkyl, an alkenyl, an alkynyl, cyano, a haloalkyl, analkoxy, a haloalkoxy, a halo, an amino, an alkylamino, a dialkylamino,—OP(O)(OR₇)₂, —SP(O)(OR₇)₂, nitro, an alkyl ester, or hydroxyl;

R₇ is —H, an optionally substituted alkyl, an optionally substitutedalkenyl, an optionally substituted alkynyl, an optionally substitutedcycloalkyl, an optionally substituted cycloalkenyl, an optionallysubstituted heterocyclyl, an optionally substituted aryl, an optionallysubstituted heteroaryl, an optionally substituted aralkyl, or anoptionally substituted heteraralkyl;

one of R_(a) or R_(b) is —H and the other is an optionally substitutedaryl or an optionally substituted heteroaryl.

In another embodiment, the invention relates to compounds of formula(IIB):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein:

one of R_(c) or R_(d) is —H and the other is an optionally substitutedheteroaryl, an unsubstituted phenyl, or a substituted phenyl representedby one of the following formulas:

R₁₈, R₁₉, R₂₂, and R₂₃, are each, independently, halo, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, an optionally substituted heteraralkyl,cyano, nitro, guanadino, a haloalkyl, a haloalkoxy, a heteroalkyl, —OR₇,—NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—OP(O)(OR₇)₂, —SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇,—S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁;

R₂₀ is an optionally substituted alkyl, an optionally substitutedalkenyl, an optionally substituted alkynyl, an optionally substitutedcycloalkyl, an optionally substituted cycloalkenyl, an optionallysubstituted heterocyclyl, an optionally substituted aryl, an optionallysubstituted heteroaryl, an optionally substituted aralkyl, an optionallysubstituted heteraralkyl, cyano, nitro, guanadino, a haloalkyl, ahaloalkoxy, a heteroalkyl, —OR₁₇, —NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇,—C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂, SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇,—OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁;

R₂₁ is halo, an optionally substituted alkyl, an optionally substitutedalkenyl, an optionally substituted alkynyl, an optionally substitutedcycloalkyl, an optionally substituted cycloalkenyl, an optionallysubstituted heterocyclyl, an optionally substituted aryl, an optionallysubstituted heteroaryl, an optionally substituted aralkyl, an optionallysubstituted heteraralkyl, cyano, nitro, guanadino, a haloalkyl, ahaloalkoxy, a heteroalkyl, —OR₁₇, —NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇,—C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂, SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇,—OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁;

R₇ and R₈, for each occurrence, are, independently, —H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, or an optionally substitutedheteraralkyl;

R₁₀ and R₁₁, for each occurrence, are independently —H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, or an optionally substitutedheteraralkyl; or R₁₀ and R₁₁, taken together with the nitrogen to whichthey are attached, form an optionally substituted heterocyclyl or anoptionally substituted heteroaryl;

R₁₇, for each occurrence, is independently, an optionally substitutedalkyl, an optionally substituted alkenyl, an optionally substitutedalkynyl, an optionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl;

p is 1 or 2; and

R^(w) is defined as for formula (IB).

In another embodiment, the invention relates to compounds of formula(IIIB):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein:

one of R_(e) or R_(f) is —H and the other is an optionally substitutedaryl or an optionally substituted heteroaryl selected from the groupconsisting of an optionally substituted 2,3-dihydro-benzo[1,4]dioxinyl,an optionally substituted benzo[1,3]dioxolyl, an optionally substitutedquinolinyl, an optionally substituted isoquinolinyl, an optionallysubstituted 1H-indolyl, an optionally substituted pyridinyl, anoptionally substituted oxazolyl, an optionally substituted isoxazolyl,an optionally substituted thiazolyl, an optionally substitutedisothiazolyl, an optionally substituted imidazolyl, an optionallysubstituted pyrazolyl, an optionally substituted furanyl, an optionallysubstituted thiophenyl, an optionally substituted thiadiazolyl, anoptionally substituted oxadiazolyl, an optionally substituted chromanyl,an optionally substituted isochromanyl, an optionally substitutedpyridazinyl, an optionally substituted pyrimidinyl, an optionallysubstituted pyrazinyl, an optionally substituted benzothiophenyl, anoptionally substituted 2,3-dihydro-benzothiophenyl, an optionallysubstituted benzofuranyl, an optionally substituted2,3-dihydro-benzofuranyl, an optionally substituted 1H-benzoimidazolyl,an optionally substituted benzothiazolyl, an optionally substitutedbenzooxazolyl, an optionally substituted 1H-benzotriazolyl, anoptionally substituted 1H-indazolyl, an optionally substituted9H-purinyl, an optionally substituted pyrrolopyrimidinyl, an optionallysubstituted pyrrolopyrazinyl, an optionally substitutedpyrrolopyridazinyl, an optionally substituted imidazopyrazinyl, or anoptionally substituted imidazolpyridazinyl; and Fr is defined as forformula (IB).

In another embodiment, the invention relates to compounds of formula(IVB):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein:

one of R_(g) or R_(h) is —H and the other is:

-   -   i) an unsubstituted phenyl or a substituted phenyl represented        by one of the following formulas:

-   -    or    -   ii) an optionally substituted heteroaryl selected from the group        consisting of an optionally substituted        2,3-dihydro-benzo[1,4]dioxinyl, an optionally substituted        benzo[1,3]dioxolyl, an optionally substituted quinolinyl, an        optionally substituted isoquinolinyl, an optionally substituted        1H-indolyl, an optionally substituted pyridinyl, an optionally        substituted oxazolyl, an optionally substituted isoxazolyl, an        optionally substituted thiazolyl, an optionally substituted        isothiazolyl, an optionally substituted imidazolyl, an        optionally substituted pyrazolyl, an optionally substituted        furanyl, an optionally substituted thiophenyl, an optionally        substituted thiadiazolyl, an optionally substituted oxadiazolyl,        an optionally substituted chromanyl, an optionally substituted        isochromanyl, an optionally substituted pyridazinyl, an        optionally substituted pyrimidinyl, an optionally substituted        pyrazinyl, an optionally substituted benzothiophenyl, an        optionally substituted 2,3-dihydro-benzothiophenyl, an        optionally substituted benzofuranyl, an optionally substituted        2,3-dihydro-benzofuranyl, an optionally substituted        1H-benzoimidazolyl, an optionally substituted benzothiazolyl, an        optionally substituted benzooxazolyl, an optionally substituted        1H-benzotriazolyl, an optionally substituted 1H-indazolyl, an        optionally substituted 9H-purinyl, an optionally substituted        pyrrolopyrimidinyl, an optionally substituted pyrrolopyrazinyl,        an optionally substituted pyrrolopyridazinyl, an optionally        substituted imidazopyrazinyl, or an optionally substituted        imidazolpyridazinyl; and

R₇ and R₈, for each occurrence, are, independently, —H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, or an optionally substitutedheteraralkyl;

R₁₀ and R₁₁, for each occurrence, are independently —H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, or an optionally substitutedheteraralkyl; or R₁₀ and R₁₁, taken together with the nitrogen to whichthey are attached, form an optionally substituted heterocyclyl or anoptionally substituted heteroaryl;

R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, and R₂₃, are defined as for formula (IIB);

R^(w) is defined as for formula (IB); and

p is 1 or 2.

In another embodiment, the invention relates to compounds of formula(VB):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein:

one of R_(i) or R_(j) is —H and the other is represented by thefollowing formula:

X₁ and X₂ are each, independently, CH or N;

R₁₂, R₁₃ and R₁₄ are each, independently, halo, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, an optionally substituted heteraralkyl,cyano, nitro, guanadino, a haloalkyl, a haloalkoxy, a heteroalkyl, —OR₇,—NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—OP(O)(OR₇)₂, —SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇,—S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁;

R^(w) is defined as for formula (IB); and

R₇, R₈, R₁₀, R₁₁, and p are defined as for formula (IIB).

In another embodiment, the invention relates to compounds of formula(VIB):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein:

one of R_(k) or R_(l) is —H and the other is represented by thefollowing formula:

the dashed line indicates that the bond is a single bond or a doublebond;

X₃ and X₄ are each, independently, CH, N, CH₂, NR₁₈, O, or S;

X₅ and X₆ are each, independently, CR₂₉ or N;

R₁₅ is H, halo, an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, anoptionally substituted heteraralkyl, cyano, nitro, guanadino, ahaloalkyl, a haloalkoxy, a heteroalkyl, —OR₁₇, —NR₁₀R₁₁, —C(O)R₇,—C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂, SP(O)(OR₇)₂,—SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or—S(O)_(p)NR₁₀R₁₁;

R₇, R₈, R₁₉, R₁₁, R₁₇, and p are defined as for formula (IIB);

R₁₆ is H, an alkyl, a cycloalkyl, an aralkyl, —C(O)R, wherein R is analkyl, a cycloalkyl, or an aralkyl;

R^(w) is defined as for formula (IB); and

R₂₉, for each occurrence, is independently, H or a substituent.

In another embodiment, the invention relates to compounds of formula(VIIB):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein:

one of R_(m) or R_(n) is —H and the other is represented by thefollowing formula:

X₁ and X₂ are each, independently, CH or N;

R^(w) is defined as for formula (IB); and

R₁₈, R₁₉, and R₂₀ are defined as for formula (IIB).

In another embodiment, the invention relates to compounds of formula(VIIIB):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein:

one of R_(o) or R_(p) is —H and the other is represented by thefollowing formula:

X₁ and X₂ are each, independently, CH or N;

R^(w) is defined as for formula (IB); and

R₂₁, R₂₂, and R₂₃ are defined as for formula (IIB).

In another embodiment, the invention relates to compounds of formula(IXB):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein:

one of R_(q) or R₁ is —H and the other is represented by the followingformula:

R^(w) is defined as for formula (IB); and

R₁₅ and R₁₉ are defined as for formula (VIB).

In another embodiment, the invention relates to compounds of formula(XB):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein:

one of R_(s) or R_(t) is —H and the other is represented by thefollowing formula:

R^(w) is defined as for formula (IB); and

R₁₅, R₁₆, and R₂₉ are defined as for formula (VIB).

In some embodiments, in the compounds represented by formula (I), (IA),or (IB), one of R_(a) or R_(b) is —H and the other is an optionallysubstituted phenyl. In one aspect of this embodiment, the phenyl grouprepresented by R_(a) or R_(b) is unsubstituted. In another aspect ofthis embodiment, the phenyl group represented by R_(a) or R_(b) issubstituted with from one to five substituents independently selectedfrom a halo, an optionally substituted alkyl, an optionally substitutedalkenyl, an optionally substituted alkynyl, an optionally substitutedcycloalkyl, an optionally substituted cycloalkenyl, an optionallysubstituted heterocyclyl, an optionally substituted aryl, an optionallysubstituted heteroaryl, an optionally substituted aralkyl, an optionallysubstituted heteraralkyl, cyano, nitro, guanadino, a haloalkyl, ahaloalkoxy, a heteroalkyl, —OR₇, —NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇,—C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇,—OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁, whereinR₇, R₈, R₁₀, R₁₁, and p are defined as above. In another aspect of thisembodiment, the phenyl group represented by R_(a) or R_(b) issubstituted with from one to five substituents, independently, selectedfrom an alkyl, an alkenyl, an alkynyl, cyano, a haloalkyl, an alkoxy, ahaloalkoxy, a halo, an amino, an alkylamino, a dialkylamino,—OP(O)(OR₇)₂, —SP(O)(OR₇)₂, nitro, an alkyl ester, or hydroxyl.Preferably, the phenyl group represented by R_(a) or R_(b) issubstituted with from one to three substituents. More preferably, thephenyl group represented by R_(a) or R_(b) is substituted with threesubstituents.

In some embodiments, in the compounds represented by formula (I), (IA),(IB), one of R_(a) or R_(b) is —H and the other is an optionallysubstituted pyridinyl. In one aspect of this embodiment, the pyridinylgroup represented by R_(a) or R_(b) is unsubstituted. In another aspectof this embodiment, the pyridinyl group represented by R_(a) or R_(b) issubstituted with one or more substituents independently selected from ahalo, an optionally substituted alkyl, an optionally substitutedalkenyl, an optionally substituted alkynyl, an optionally substitutedcycloalkyl, an optionally substituted cycloalkenyl, an optionallysubstituted heterocyclyl, an optionally substituted aryl, an optionallysubstituted heteroaryl, an optionally substituted aralkyl, an optionallysubstituted heteraralkyl, cyano, nitro, guanadino, a haloalkyl, ahaloalkoxy, a heteroalkyl, —OR₇, —NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇,—C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇,—OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁, whereinR₇, R₈, R₁₀, R₁₁, and p are defined as above. In another aspect of thisembodiment, the pyridinyl group represented by R_(a) or R_(b) issubstituted with one or more substituents, independently, selected froman alkyl, an alkenyl, an alkynyl, cyano, a haloalkyl, an alkoxy, ahaloalkoxy, a halo, an amino, an alkylamino, a dialkylamino,—OP(O)(OR₇)₂, —SP(O)(OR₇)₂, nitro, an alkyl ester, or hydroxyl.Preferably, the pyridinyl group represented by R_(a) or R_(b) issubstituted with from one to three substituents. More preferably, thepyridinyl group represented by R_(a) or R_(b) is substituted with threesubstituents.

In some embodiments, in the compounds represented by formula (I), (IA),or (IB), one of R_(a) or R_(b) is —H and the other is an optionallysubstituted benzo[1,3]dioxolyl. In one aspect of this embodiment, thebenzo[1,3]dioxolyl group represented by R_(a) or R_(b) is unsubstituted.In another aspect of this embodiment, the benzo[1,3]dioxolyl grouprepresented by R_(a) or R_(b) is substituted with one or moresubstituents independently selected from a halo, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, an optionally substituted heteraralkyl,cyano, nitro, guanadino, a haloalkyl, a haloalkoxy, a heteroalkyl, —OR₇,—NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—OP(O)(OR₇)₂, —SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇,—S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁, wherein R₇, R₈, R₁₀,R₁₁, and p are defined as above. In another aspect of this embodiment,the benzo[1,3]dioxolyl group represented by R_(a) or R_(b) issubstituted with one or more substituents, independently, selected froman alkyl, an alkenyl, an alkynyl, cyano, a haloalkyl, an alkoxy, ahaloalkoxy, a halo, an amino, an alkylamino, a dialkylamino,—OP(O)(OR₇)₂, —SP(O)(OR₇)₂, nitro, an alkyl ester, or hydroxyl.Preferably, the benzo[1,3]dioxolyl group represented by R_(a) or R_(b)is substituted with from one to three substituents. More preferably, thebenzo[1,3]dioxolyl group represented by R_(a) or R_(b) is substitutedwith one substituent.

In some embodiments, in the compounds represented by formula (I), (IA),or (IB), R_(a) or R_(b) is —H and the other is an optionally substituted1H-indolyl. In one aspect of this embodiment, the 1H-indolyl grouprepresented by R_(a) or R_(b) is unsubstituted. In another aspect ofthis embodiment, the 1H-indolyl group represented by R_(a) or R_(b) issubstituted with one or more substituents independently selected from ahalo, an optionally substituted alkyl, an optionally substitutedalkenyl, an optionally substituted alkynyl, an optionally substitutedcycloalkyl, an optionally substituted cycloalkenyl, an optionallysubstituted heterocyclyl, an optionally substituted aryl, an optionallysubstituted heteroaryl, an optionally substituted aralkyl, an optionallysubstituted heteraralkyl, cyano, nitro, guanadino, a haloalkyl, ahaloalkoxy, a heteroalkyl, —OR₇, —NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇,—C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇,—OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁, whereinR₇, R₈, R₁₀, R₁₁, and p are defined as above. In another aspect of thisembodiment, the 1H-indolyl group represented by R_(a) or R_(b) issubstituted with one or more substituents, independently, selected froman alkyl, an alkenyl, an alkynyl, cyano, a haloalkyl, an alkoxy, ahaloalkoxy, a halo, an amino, an alkylamino, a dialkylamino,—OP(O)(OR₇)₂, —SP(O)(OR₇)₂, nitro, an alkyl ester, or hydroxyl.Preferably, the 1H-indolyl group represented by R_(a) or R_(b) issubstituted with from one to three substituents. More preferably, the1H-indolyl group represented by R_(a) or R_(b) is substituted with onesubstituent.

In some embodiments, in the compounds represented by formulas (II),(IIA), or (IIB), R_(c) or R_(d) is —H and the other is an optionallysubstituted pyridinyl. In one aspect of this embodiment, the pyridinylgroup represented by R_(c) or R_(d) is unsubstituted. In another aspectof this embodiment, the pyridinyl group represented by R_(c) or R_(d) issubstituted with one or more substituents independently selected from ahalo, an optionally substituted alkyl, an optionally substitutedalkenyl, an optionally substituted alkynyl, an optionally substitutedcycloalkyl, an optionally substituted cycloalkenyl, an optionallysubstituted heterocyclyl, an optionally substituted aryl, an optionallysubstituted heteroaryl, an optionally substituted aralkyl, an optionallysubstituted heteraralkyl, cyano, nitro, guanadino, a haloalkyl, ahaloalkoxy, a heteroalkyl, —OR₇, —NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇,—C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇,—OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁, whereinR₇, R₈, R₁₀, R₁₁, and p are defined as above. In another aspect of thisembodiment, the pyridinyl group represented by R_(c) or R_(d) issubstituted with one or more substituents, independently, selected froman alkyl, an alkenyl, an alkynyl, cyano, a haloalkyl, an alkoxy, ahaloalkoxy, a halo, an amino, an alkylamino, a dialkylamino,—OP(O)(OR₇)₂, —SP(O)(OR₇)₂, nitro, an alkyl ester, or hydroxyl.Preferably, the pyridinyl group represented by R_(c) or R_(d) issubstituted with from one to three substituents. More preferably, thepyridinyl group represented by R_(c) or R_(d) is substituted with threesubstituents.

In some embodiments, in the compounds represented by formulas (II),(IIA), or (IIB), R_(c) or R_(d) is —H and the other is an optionallysubstituted benzo[1,3]dioxolyl. In one aspect of this embodiment, thebenzo[1,3]dioxolylgroup represented by R_(c) or R_(d) is unsubstituted.In another aspect of this embodiment, the benzo[1,3]dioxolylgrouprepresented by R_(c) or R_(d) is substituted with one or moresubstituents independently selected from a halo, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, an optionally substituted heteraralkyl,cyano, nitro, guanadino, a haloalkyl, a haloalkoxy, a heteroalkyl, —OR₇,—NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—OP(O)(OR₇)₂, —SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇,—S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁, wherein R₇, R₈, R₁₀,R₁₁, and p are defined as above. In another aspect of this embodiment,the benzo[1,3]dioxolylgroup represented by R_(c) or R_(d) is substitutedwith one or more substituents, independently, selected from an alkyl, analkenyl, an alkynyl, cyano, a haloalkyl, an alkoxy, a haloalkoxy, ahalo, an amino, an alkylamino, a dialkylamino, —OP(O)(OR₇)₂,—SP(O)(OR₇)₂, nitro, an alkyl ester, or hydroxyl. Preferably, thebenzo[1,3]dioxolylgroup represented by R_(c) or R_(d) is substitutedwith from one to three substituents. More preferably, thebenzo[1,3]dioxolylgroup represented by R_(c) or R_(d) is substitutedwith one substituent.

In some embodiments, in the compounds represented by formulas (II),(IIA), or (IIB), R_(c) or R_(d) is —H and the other is an optionallysubstituted 1H-indolyl. In one aspect of this embodiment, the 1H-indolylgroup represented by R_(c) or R_(d) is unsubstituted. In another aspectof this embodiment, the 1H-indolyl group represented by R_(c) or R_(d)is substituted with one or more substituents independently selected froma halo, an optionally substituted alkyl, an optionally substitutedalkenyl, an optionally substituted alkynyl, an optionally substitutedcycloalkyl, an optionally substituted cycloalkenyl, an optionallysubstituted heterocyclyl, an optionally substituted aryl, an optionallysubstituted heteroaryl, an optionally substituted aralkyl, an optionallysubstituted heteraralkyl, cyano, nitro, guanadino, a haloalkyl, ahaloalkoxy, a heteroalkyl, —OR₇, —NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇,—C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇,—OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁, whereinR₇, R₈, R₁₀, R₁₁, and p are defined as above. In another aspect of thisembodiment, the 1H-indolyl group represented by R_(c) or R_(d) issubstituted with one or more substituents, independently, selected froman alkyl, an alkenyl, an alkynyl, cyano, a haloalkyl, an alkoxy, ahaloalkoxy, a halo, an amino, an alkylamino, a dialkylamino,—OP(O)OR₇)₂, —SP(O)(OR₇)₂, nitro, an alkyl ester, or hydroxyl.Preferably, the 1H-indolyl group represented by R_(c) or R_(d) issubstituted with from one to three substituents. More preferably, the1H-indolyl group represented by R_(c) or R_(d) is substituted with onesubstituent.

In some embodiments, in the compounds represented by formulas (III),(IIIA), or (IIIB), R_(e) or R_(f) is —H and the other is an optionallysubstituted phenyl. In one aspect of this embodiment, the phenyl grouprepresented by R_(e) or R_(f) is unsubstituted. In another aspect ofthis embodiment, the phenyl group represented by R_(e) or R_(f) issubstituted with from one to five substituents independently selectedfrom a halo, an optionally substituted alkyl, an optionally substitutedalkenyl, an optionally substituted alkynyl, an optionally substitutedcycloalkyl, an optionally substituted cycloalkenyl, an optionallysubstituted heterocyclyl, an optionally substituted aryl, an optionallysubstituted heteroaryl, an optionally substituted aralkyl, an optionallysubstituted heteraralkyl, cyano, nitro, guanadino, a haloalkyl, ahaloalkoxy, a heteroalkyl, —OR₇, —NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇,—C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇,—OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁, whereinR₇, R₈, R₁₀, R₁₁, and p are defined as above. In another aspect of thisembodiment, the phenyl group represented by R_(e) or R_(f) issubstituted with from one to five substituents, independently, selectedfrom an alkyl, an alkenyl, an alkynyl, cyano, a haloalkyl, an alkoxy, ahaloalkoxy, a halo, an amino, an alkylamino, a dialkylamino,—OP(O)(OR₇)₂, —SP(O)(OR₇)₂, nitro, an alkyl ester, or hydroxyl.Preferably, the phenyl group represented by R_(e) or R_(f) issubstituted with from one to three substituents. More preferably, thephenyl group represented by R_(e) or R_(f) is substituted with threesubstituents.

In some embodiments, in the compounds represented by formulas (III),(IIIA), or (IIIB), R_(e) or R_(f) is —H and the other is an optionallysubstituted pyridinyl. In one aspect of this embodiment, the pyridinylgroup represented by R_(e) or R_(f) is unsubstituted. In another aspectof this embodiment, the pyridinyl group represented by R_(e) or R_(f) issubstituted with one or more substituents independently selected from ahalo, an optionally substituted alkyl, an optionally substitutedalkenyl, an optionally substituted alkynyl, an optionally substitutedcycloalkyl, an optionally substituted cycloalkenyl, an optionallysubstituted heterocyclyl, an optionally substituted aryl, an optionallysubstituted heteroaryl, an optionally substituted aralkyl, an optionallysubstituted heteraralkyl, cyano, nitro, guanadino, a haloalkyl, ahaloalkoxy, a heteroalkyl, —OR₇, —NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇,—C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇,—OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁, whereinR₇, R₈, R₁₀, R₁₁, and p are defined as above. In another aspect of thisembodiment, the pyridinyl group represented by R_(e) or R_(f) issubstituted with one or more substituents, independently, selected froman alkyl, an alkenyl, an alkynyl, cyano, a haloalkyl, an alkoxy, ahaloalkoxy, a halo, an amino, an alkylamino, a dialkylamino,—OP(O)(OR₇)₂, —SP(O)(OR₇)₂, nitro, an alkyl ester, or hydroxyl.Preferably, the pyridinyl group represented by R_(e) or R_(f) issubstituted with from one to three substituents. More preferably, thepyridinyl group represented by R_(e) or R_(f) is substituted with threesubstituents.

In some embodiments, in the compounds represented by formulas (III),(IIIA), or (IIIB), R_(e) or R_(f) is —H and the other is an optionallysubstituted benzo[1,3]dioxolyl. In one aspect of this embodiment, thebenzo[1,3]dioxolylgroup represented by R_(e) or R_(f) is unsubstituted.In another aspect of this embodiment, the benzo[1,3]dioxolylgrouprepresented by R_(e) or R_(f) is substituted with one or moresubstituents independently selected from a halo, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, an optionally substituted heteraralkyl,cyano, nitro, guanadino, a haloalkyl, a haloalkoxy, a heteroalkyl, —OR₇,—NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—OP(O)(OR₇)₂, —SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇,—S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁, wherein R₇, R₈, R₁₀,R₁₁, and p are defined as above. In another aspect of this embodiment,the benzo[1,3]dioxolylgroup represented by R_(e) or R_(f) is substitutedwith one or more substituents, independently, selected from an alkyl, analkenyl, an alkynyl, cyano, a haloalkyl, an alkoxy, a haloalkoxy, ahalo, an amino, an alkylamino, a dialkylamino, —OP(O)(OR₇)₂,—SP(O)(OR₇)₂, nitro, an alkyl ester, or hydroxyl. Preferably, thebenzo[1,3]dioxolylgroup represented by R_(e) or R_(f) is substitutedwith from one to three substituents. More preferably, thebenzo[1,3]dioxolylgroup represented by R_(e) or R_(f) is substitutedwith one substituent.

In some embodiments, in the compounds represented by formulas (III),(IIIA), or (IIIB), R_(e) or R_(f) is —H and the other is an optionallysubstituted 1H-indolyl. In one aspect of this embodiment, the 1H-indolylgroup represented by R_(e) or R_(f) is unsubstituted. In another aspectof this embodiment, the 1H-indolyl group represented by R_(e) or R_(f)is substituted with one or more substituents independently selected froma halo, an optionally substituted alkyl, an optionally substitutedalkenyl, an optionally substituted alkynyl, an optionally substitutedcycloalkyl, an optionally substituted cycloalkenyl, an optionallysubstituted heterocyclyl, an optionally substituted aryl, an optionallysubstituted heteroaryl, an optionally substituted aralkyl, an optionallysubstituted heteraralkyl, cyano, nitro, guanadino, a haloalkyl, ahaloalkoxy, a heteroalkyl, —OR₇, —NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇,—C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇,—OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(g)R₇, or —S(O)_(p)NR₁₀R₁₁, whereinR₇, R₈, R₁₀, R₁₁, and p are defined as above. In another aspect of thisembodiment, the 1H-indolyl group represented by R_(e) or R_(f) issubstituted with one or more substituents, independently, selected froman alkyl, an alkenyl, an alkynyl, cyano, a haloalkyl, an alkoxy, ahaloalkoxy, a halo, an amino, an alkylamino, a dialkylamino,—OP(O)(OR₇)₂, —SP(O)(OR₇)₂, nitro, an alkyl ester, or hydroxyl.Preferably, the 1H-indolyl group represented by R_(e) or R_(f) issubstituted with from one to three substituents. More preferably, the1H-indolyl group represented by R_(e) or R_(f) is substituted with onesubstituent.

In some embodiments, in the compounds represented by formulas (IV),(IVA), or (IVB), R_(g) or R_(h) is —H and the other is an optionallysubstituted pyridinyl. In one aspect of this embodiment, the pyridinylgroup represented by R_(g) or R_(h) is unsubstituted. In another aspectof this embodiment, the pyridinyl group represented by R_(g) or R_(h) issubstituted with one or more substituents independently selected from ahalo, an optionally substituted alkyl, an optionally substitutedalkenyl, an optionally substituted alkynyl, an optionally substitutedcycloalkyl, an optionally substituted cycloalkenyl, an optionallysubstituted heterocyclyl, an optionally substituted aryl, an optionallysubstituted heteroaryl, an optionally substituted aralkyl, an optionallysubstituted heteraralkyl, cyano, nitro, guanadino, a haloalkyl, ahaloalkoxy, a heteroalkyl, —OR₇, —NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇,—C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇,—OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁, whereinR₇, R₈, R₁₀, R₁₁, and p are defined as above. In another aspect of thisembodiment, the pyridinyl group represented by R_(g) or R_(h) issubstituted with one or more substituents, independently, selected froman alkyl, an alkenyl, an alkynyl, cyano, a haloalkyl, an alkoxy, ahaloalkoxy, a halo, an amino, an alkylamino, a dialkylamino,—OP(O)(OR₇)₂, —SP(O)(OR₇)₂, nitro, an alkyl ester, or hydroxyl.Preferably, the pyridinyl group represented by R_(g) or R_(h) issubstituted with from one to three substituents. More preferably, thepyridinyl group represented by R_(g) or R_(h) is substituted with threesubstituents.

In some embodiments, in the compounds represented by formulas (IV),(IVA), or (IVB), R_(g) or R_(h) is —H and the other is an optionallysubstituted benzo[1,3]dioxolyl. In one aspect of this embodiment, thebenzo[1,3]dioxolyl group represented by R_(g) or R_(h) is unsubstituted.In another aspect of this embodiment, the benzo[1,3]dioxolyl grouprepresented by R_(g) or R_(h) is substituted with one or moresubstituents independently selected from a halo, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, an optionally substituted heteraralkyl,cyano, nitro, guanadino, a haloalkyl, a haloalkoxy, a heteroalkyl, —OR₇,—NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—OP(O)(OR₇)₂, —SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇,—S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁, wherein R₇, R₈, R₁₀,R₁₁, and p are defined as above. In another aspect of this embodiment,the benzo[1,3]dioxolyl group represented by R_(g) or R_(h) issubstituted with one or more substituents, independently, selected froman alkyl, an alkenyl, an alkynyl, cyano, a haloalkyl, an alkoxy, ahaloalkoxy, a halo, an amino, an alkylamino, a dialkylamino,—OP(O)(OR₇)₂, —SP(O)(OR₇)₂, nitro, an alkyl ester, or hydroxyl.Preferably, the benzo[1,3]dioxolyl group represented by R_(g) or R_(h)is substituted with from one to three substituents. More preferably, thebenzo[1,3]dioxolyl group represented by R_(g) or R_(h) is substitutedwith one substituent.

In some embodiments, in the compounds represented by formulas (IV),(IVA), or (IVB), R_(g) or R_(h) is —H and the other is an optionallysubstituted 1H-indolyl. In one aspect of this embodiment, the 1H-indolylgroup represented by R_(g) or R_(h) is unsubstituted. In another aspectof this embodiment, the 1H-indolyl group represented by R_(g) or R_(h)is substituted with one or more substituents independently selected froma halo, an optionally substituted alkyl, an optionally substitutedalkenyl, an optionally substituted alkynyl, an optionally substitutedcycloalkyl, an optionally substituted cycloalkenyl, an optionallysubstituted heterocyclyl, an optionally substituted aryl, an optionallysubstituted heteroaryl, an optionally substituted aralkyl, an optionallysubstituted heteraralkyl, cyano, nitro, guanadino, a haloalkyl, ahaloalkoxy, a heteroalkyl, —OR₇, —NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇,—C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇,—OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁, whereinR₇, R₈, R₁₀, R₁₁, and p are defined as above. In another aspect of thisembodiment, the 1H-indolyl group represented by R_(g) or R_(h) issubstituted with one or more substituents, independently, selected froman alkyl, an alkenyl, an alkynyl, cyano, a haloalkyl, an alkoxy, ahaloalkoxy, a halo, an amino, an alkylamino, a dialkylamino,—OP(O)(OR₇)₂, —SP(O)(OR₇)₂, nitro, an alkyl ester, or hydroxyl.Preferably, the 1H-indolyl group represented by R_(g) or R_(h) issubstituted with from one to three substituents. More preferably, the1H-indolyl group represented by R_(g) or R_(h) is substituted with onesubstituent.

In some embodiments, in the compounds represented by formulas (I),(III), or (V), R₂ is an optionally substituted phenyl. In one aspect ofthis embodiment, the phenyl group represented by R₂ is unsubstituted. Inanother aspect of this embodiment, the phenyl group represented by R₂ issubstituted with from one to five groups independently selected fromalkoxy, halo, alkyl, haloalkyl, haloalkoxy, nitro, cyano, oxazolyl,1H-tetrazolyl, 1-methyl-1H-tetrazolyl, —OR₂₄, —SR₂₄, —C(O)R₂₄,—C(O)OR₂₄, —OC(O)R₂₄, —C(O)NR₂₅R₂₆, —NR₂₄C(O)R₂₇, —NR₂₄C(O)OR₂₇,—OC(O)NR₂₅R₂₆, guanidino, amino, alkyl amino, dialkylamino,—NR₂₄S(O)_(p)R₂₈, —S(O)_(p)R₂₈, —S(O)_(p)OR₂₇, —OS(O)_(p)R₂₈,—OS(O)_(p)OR₂₇, —OP(O)(OR₂₇)₂, or —SP(O)(OR₂₇)₂, wherein:

p is defined as above;

R₂₄ and R₂₇, for each occurrence are, independently, H, an alkyl, or acycloalkyl;

R₂₅ and R₂₆, for each occurrence are, independently, H, an alkyl, or acycloalkyl; or

R₂₅ and R₂₆, together with the nitrogen to which they are attached are aheterocyclyl or a heteroaryl; and

R₂₅, for each occurrence, is an alkyl or a cycloalkyl.

In one aspect of this embodiment, the phenyl group represented by R₂ issubstituted with from one to three substituents. In one aspect of thisembodiment, the phenyl group represented by R₂ is substituted with twosubstituents. In one aspect, the phenyl is substituted with one aminogroup and one alkoxy group. In one aspect of this embodiment, the phenylrepresented by R₂ is substituted with one substituent.

In some embodiments, in the compounds represented by formulas (I),(III), or (V), R₂ is an optionally substituted pyridinyl. In one aspectof this embodiment, the pyridinyl group represented by R₂ isunsubstituted. In another aspect of this embodiment, the pyridinyl grouprepresented by R₂ is substituted with one or more substituentsindependently selected from alkoxy, halo, alkyl, haloalkyl, haloalkoxy,nitro, cyano, oxazolyl, 1H-tetrazolyl, 1-methyl-1H-tetrazolyl, —OR₂₄,—SR₂₄, —C(O)R₂₄, —C(O)OR₂₄, —OC(O)R₂₄, —C(O)NR₂₅R₂₆, —NR₂₄C(O)R₂₇,—NR₂₄C(O)OR₂₇, —OC(O)NR₂₅R₂₆, guanidino, amino, alkyl amino,dialkylamino, —NR₂₄S(O)_(p)R₂₈, —S(O)_(p)R₂₈, —S(O)_(p)OR₂₇,—OS(O)_(p)R₂₈, —OS(O)_(p)OR₂₇, —OP(O)(OR₂₇)₂, or —SP(O)(OR₂₇)₂, whereinR₂₄, R₂₅, R₂₆, R₂₇, R₂₈ and p are defined as above. In one aspect ofthis embodiment, the pyridinyl group represented by R₂ is substitutedwith from one to three substituents. Preferably, the pyridinylrepresented by R₂ is substituted with one substituent.

In some embodiments, in the compounds represented by formulas (I),(III), or (V), R₂ is an optionally substituted2,3-dihydro-benzo[1,4]dioxinyl, an optionally substituted biphenyl, anoptionally substituted pyridinyl-phenyl, an optionally substitutedpyridinyl, an optionally substituted quinolinyl, an optionallysubstituted isoquinolinyl, an optionally substituted 1H-indolyl, anoptionally substituted oxazolyl, an optionally substitutedbenzo[1,3]dioxolyl, an optionally substituted pyridazinyl, an optionallysubstituted pyrimidinyl, or an optionally substituted benzofuranyl. Inone aspect of this embodiment, R₂ is unsubstituted. In another aspect ofthis embodiment, R₂ is substituted with one or more substituentsindependently selected from alkoxy, halo, alkyl, haloalkyl, haloalkoxy,nitro, cyano, oxazolyl, 1H-tetrazolyl, 1-methyl-1H-tetrazolyl, —OR₂₄,—SR₂₄, —C(O)R₂₄, —C(O)OR₂₄, —OC(O)R₂₄, —C(O)NR₂₅R₂₆, —NR₂₄C(O)R₂₇,—NR₂₄C(O)OR₂₇, —OC(O)NR₂₅R₂₆, guanidino, amino, alkyl amino,dialkylamino, —NR₂₄S(O)_(p)R₂₈, —S(O)_(p)R₂₈, —S(O)_(p)OR₂₇,—OS(O)_(p)R₂₈, —OS(O)_(p)OR₂₇, —OP(O)(OR₂₇)₂, or —SP(O)(OR₂₇)₂, whereinR₂₄, R₂₅, R₂₆, R₂₇, R₂₈ and p are defined as above. In one aspect ofthis embodiment, R₂ is substituted with from one to three substituents.Preferably, R₂ is substituted with one substituent.

In some embodiments, in the compounds represented by formula (II), (IV),(VI), (VII), (VIII), (IX), or (X), R₄ is an optionally substitutedphenyl. In one aspect of this embodiment, the phenyl group representedby R₄ is unsubstituted. In another aspect of this embodiment, the phenylgroup represented by R₄ is substituted with from one to five groupsindependently selected from alkoxy, halo, alkyl, haloalkyl, haloalkoxy,nitro, cyano, oxazolyl, 1H-tetrazolyl, 1-methyl-1H-tetrazolyl, —OR₂₄,—SR₂₄, —C(O)R₂₄, —C(O)OR₂₄, —OC(O)R₂₄, —C(O)NR₂₅R₂₆, —NR₂₄C(O)R₂₇,—NR₂₄C(O)OR₂₇, —OC(O)NR₂₅R₂₆, guanidino, amino, alkyl amino,dialkylamino, —NR₂₄S(O)_(p)R₂₈, —S(O)_(p)R₂₈, —S(O)_(p)OR₂₇,—OS(O)_(p)R₂₈, —OS(O)_(p)OR₂₇, —OP(O)(OR₂₇)₂, or —SP(O)(OR₂₇)₂, whereinR₂₄, R₂₅, R₂₆, R₂₇, R₂₈ and p are defined as above. In one aspect ofthis embodiment, the phenyl group represented by R₄ is substituted withfrom one to three substituents. In one aspect of this embodiment, thephenyl group represented by R₄ is substituted with two substituents. Inone aspect, the phenyl is substituted with one amino group and onealkoxy group. In one aspect, the phenyl represented by R₄ is substitutedwith one substituent.

In some embodiments, in the compounds represented by formula (II), (IV),(VI), (VII), (VIII), (IX), or (X), R₄ is an optionally substitutedpyridinyl. In one aspect of this embodiment, the pyridinyl grouprepresented by R₄ is unsubstituted. In another aspect of thisembodiment, the pyridinyl group represented by R₄ is substituted withone or more substituents independently selected from alkoxy, halo,alkyl, haloalkyl, haloalkoxy, nitro, cyano, oxazolyl, 1H-tetrazolyl,1-methyl-1H-tetrazolyl, —OR₂₄, —SR₂₄, —C(O)R₂₄, —C(O)OR₂₄, —OC(O)R₂₄,—C(O)NR₂₅R₂₆, —NR₂₄C(O)R₂₇, —NR₂₄C(O)OR₂₇, —OC(O)NR₂₅R₂₆, guanidino,amino, alkyl amino, dialkylamino, —NR₂₄S(O)_(p)R₂₈, —S(O)_(p)R₂₈,—S(O)_(p)OR₂₇, —OS(O)_(p)R₂₈, —OS(O)_(p)OR₂₇, —OP(O)(OR₂₇)₂, or—SP(O)(OR₂₇)₂, wherein R₂₄, R₂₅, R₂₆, R₂₇, R₂₈ and p are defined asabove. In one aspect of this embodiment, the pyridinyl group representedby R₄ is substituted with from one to three substituents. Preferably,the pyridinyl represented by R₄ is substituted with one substituent.

In some embodiments, in the compounds represented by formula (II), (IV),(VI), (VII), (VIII), (IX), or (X), R₄ is an optionally substituted2,3-dihydro-benzo[1,4]dioxinyl, an optionally substituted biphenyl, anoptionally substituted pyridinyl-phenyl, an optionally substitutedpyridinyl, an optionally substituted quinolinyl, an optionallysubstituted isoquinolinyl, an optionally substituted 1H-indolyl, anoptionally substituted oxazolyl, an optionally substitutedbenzo[1,3]dioxolyl, an optionally substituted pyridazinyl, an optionallysubstituted pyrimidinyl, or an optionally substituted benzofuranyl. Inone aspect of this embodiment, R₄ is unsubstituted. In another aspect ofthis embodiment, R₄ is substituted with one or more substituentsindependently selected from alkoxy, halo, alkyl, haloalkyl, haloalkoxy,nitro, cyano, oxazolyl, 1H-tetrazolyl, 1-methyl-1H-tetrazolyl, —OR₂₄,—SR₂₄, —C(O)R₂₄, —C(O)OR₂₄, —OC(O)R₂₄, —C(O)NR₂₅R₂₆, —NR₂₄C(O)R₂₇,—NR₂₄C(O)OR₂₇, —OC(O)NR₂₅R₂₆, guanidino, amino, alkyl amino,dialkylamino, —NR₂₄S(O)_(p)R₂₈, —S(O)_(p)R₂₈, —S(O)_(p)OR₂₇,—OS(O)_(p)R₂₈, —OS(O)_(p)OR₂₇, —OP(O)(OR₂₇)₂, or —SP(O)(OR₂₇)₂, whereinR₂₄, R₂₅, R₂₆, R₂₇, R₂₈ and p are defined as above. In one aspect ofthis embodiment, R₄ is substituted with from one to three substituents.Preferably, R₄ is substituted with one substituent.

In some embodiments, in the compounds represented by formulas (V), (VA),or (VB), R₁₂, R₁₃, and R₁₄ are each, independently, an alkyl, analkenyl, an alkynyl, cyano, a haloalkyl, an alkoxy, a haloalkoxy, ahalo, an amino, an alkylamino, a dialkylamino, —OP(O)(OR₇)₂,—SP(O)(OR₇)₂, nitro, an alkyl ester, or hydroxyl. In one aspect of thisembodiment, R₁₂, R₁₃, and R₁₄ are each, independently, an alkoxy. Inanother aspect of this embodiment, R₁₂, R₁₃, and R₁₄ are each methoxy.

In some embodiments, in the compounds represented by formulas (V), (VA),(VB), (VII), (VIIA), (VIIB), (VIII), (VIIIA), or (VIIIB), X₁ and X₂ areCH.

In some embodiments, in the compounds represented by formulas (V), (VA),(VB), (VII), (VIIA), (VIIB), (VIII), (VIIIA), or (VIIIB), X₁ and X₂ areN.

In some embodiments, in the compounds represented by formulas (V), (VA),(VB), (VII), (VIIA), (VIIB), (VIII), (VIIIA), or (VIIIB), X₁ is N and X₂is CH.

In some embodiments, in the compounds represented by formulas (V), (VA),(VB), (VII), (VIIA), (VIIB), (VIII), (VIIIA), or (VIIIB), X₁ is CH andX₂ is N.

In some embodiments, in the compounds represented by formulas (VI),(VIA), or (VIB), X₃ and X₄ are 0 and X₅ and X₆ are CH. In one aspect ofthis embodiment, X₃ and X₄ are O; X₅ and X₆ are CH; and R₁₅ is analkoxy, such as methoxy.

In some embodiments, in the compounds represented by formulas (VI),(VIA), or (VIB), X₃ is CH; X₄ are NR₁₆; and X₅ and X₆ are CH. In oneaspect of this embodiment, X₃ is CH; X₄ are NR₁₆; X₅ and X₆ are CH; andR₁₆ is H. In one aspect of this embodiment, X₃ is CH; X₄ are NR₁₆, X₅and X₆ are CH; and R₁₆ is a lower alkyl.

In some embodiments, in the compounds represented by formulas (VI),(VIA), (VIB), (IX), (IXA), (IXB), (X), (XA), or (XB), R₁₅ is H, alkoxy,halo, alkyl, haloalkyl, haloalkoxy, nitro, cyano, —SR₂₄, —C(O)R₂₄,—C(O)OR₂₄, —OC(O)R₂₄, —C(O)NR₂₅R₂₆, —NR₂₄C(O)R₂₇, —NR₂₄C(O)OR₂₇,—OC(O)NR₂₅R₂₆, guanidino, amino, alkylamino, dialkylamino,—NR₂₄S(O)_(p)R₂₈, —S(O)_(p)R₂₈, —S(O)_(p)OR₂₇, —OS(O)_(p)R₂₈,—OS(O)_(p)OR₂₇, —OP(O)(OR₂₇)₂, or —SP(O)(OR₂₇)₂; wherein R₂₄, R₂₅, R₂₆,R₂₇, R₂₈, and p are defined as above.

In some embodiments, in the compounds represented by formulas (IX),(IXA), (IXB), (X), (XA) or (XB), R₁₅ is H, alkoxy, halo, alkyl,haloalkyl, haloalkoxy, nitro, cyano, —SR₂₄, —C(O)R₂₄, —C(O)OR₂₄,—OC(O)R₂₄, —C(O)NR₂₅R₂₆, —NR₂₄C(O)R₂₇, —NR₂₄C(O)OR₂₇, —OC(O)NR₂₅R₂₆,guanidino, amino, alkylamino, dialkylamino, —NR₂₄S(O)_(p)R₂₈,—S(O)_(p)R₂₈, —S(O)_(p)OR₂₇, —OS(O)_(p)R₂₈, —OS(O)_(p)OR₂₇,—OP(O)(OR₂₇)₂, or —SP(O)(OR₂₇)₂; and R₂₉, for each occurrence, isindependently, H, alkoxy, halo, alkyl, haloalkyl, haloalkoxy, nitro,cyano, —OR₂₄, —SR₂₄, —C(O)R₂₄, —C(O)OR₂₄, —OC(O)R₂₄, —C(O)NR₂₅R₂₆,—NR₂₄C(O)R₂₇, —NR₂₄C(O)OR₂₇, —OC(O)NR₂₅R₂₆, guanidino, amino, alkylamino, dialkylamino, —NR₂₄S(O)_(p)R₂₈, —S(O)_(p)R₂₈, —S(O)_(p)OR₂₇,—OS(O)_(p)R₂₈, —OS(O)_(p)OR₂₇, —OP(O)(OR₂₇)₂, or —SP(O)(OR₂₇)₂; whereinR₂₄, R₂₅, R₂₆, R₂₇, R₂₈, and p are defined as above.

In some embodiments, in the compounds represented by formulas (VII),(VIIA), or (VIIB), R₁₈ and R₁₉ are each, independently, an alkyl, analkenyl, an alkynyl, cyano, a haloalkyl, an alkoxy, a haloalkoxy, ahalo, an amino, an alkylamino, a dialkylamino, —OP(O)(OR₇)₂,—SP(O)(OR₇)₂, nitro, an alkyl ester, or hydroxyl; and R₂₀ is an alkyl,an alkenyl, an alkynyl, cyano, a haloalkyl, an alkoxy, a haloalkoxy, ahalo, an amino, an alkylamino, a dialkylamino, —OP(O)(OR₇)₂,—SP(O)(OR₇)₂, nitro, or an alkyl ester; wherein R₇ is defined as above.

In some embodiments, in the compounds represented by formulas (II),(IIA) or (IIB), R_(c) or R_(d) is —H and the other is a substitutedphenyl represented by the following structural formula:

and

R₁₈ and R₁₉ are each, independently, an alkyl, an alkenyl, an alkynyl,cyano, a haloalkyl, an alkoxy, a haloalkoxy, a halo, an amino, analkylamino, a dialkylamino, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂, nitro, an alkylester, or hydroxyl; and R₂₀ is an alkyl, an alkenyl, an alkynyl, cyano,a haloalkyl, an alkoxy, a haloalkoxy, a halo, an amino, an alkylamino, adialkylamino, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂, nitro, or an alkyl ester;wherein R₇ is defined as above and “}” represents the point ofattachment of the phenyl ring to the isoxazole ring.

In some embodiments, in the compounds represented by formulas (IV),(IVA), or (IVB), R_(g) or R_(h) is —H and the other is a substitutedphenyl represented by the following structural formula:

and

R₁₈ and R₁₉ are each, independently, an alkyl, an alkenyl, an alkynyl,cyano, a haloalkyl, an alkoxy, a haloalkoxy, a halo, an amino, analkylamino, a dialkylamino, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂, nitro, an alkylester, or hydroxyl; and R₂₀ is an alkyl, an alkenyl, an alkynyl, cyano,a haloalkyl, an alkoxy, a haloalkoxy, a halo, an amino, an alkylamino, adialkylamino, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂, nitro, or an alkyl ester;wherein R₇ is defined as above and “}” represents the point ofattachment of the phenyl ring to the isoxazole ring.

In some embodiments, in the compounds represented by formulas (VIII),(VIIIA), or (VIIIB), R₂₂ and R₂₃ are each, independently, an alkyl, analkenyl, an alkynyl, cyano, a haloalkyl, an alkoxy, a haloalkoxy, ahalo, an amino, an alkylamino, a dialkylamino, —OP(O)(OR₇)₂,—SP(O)(OR₇)₂, nitro, an alkyl ester, or hydroxyl; and R₂₁ is an alkyl,an alkenyl, an alkynyl, cyano, a haloalkyl, an alkoxy, a haloalkoxy, ahalo, an amino, an alkylamino, a dialkylamino, —OP(O)(OR₇)₂,—SP(O)(OR₇)₂, nitro, or an alkyl ester, wherein R₇ is defined as above.

In some embodiments, in the compounds represented by formulas (II),(IIA), or (IIB), R_(c) or R_(d) is —H and the other is a substitutedphenyl represented by the following structural formula:

and

R₂₂ and R₂₃ are each, independently, an alkyl, an alkenyl, an alkynyl,cyano, a haloalkyl, an alkoxy, a haloalkoxy, a halo, an amino, analkylamino, a dialkylamino, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂, nitro, an alkylester, or hydroxyl; and R₂₁ is an alkyl, an alkenyl, an alkynyl, cyano,a haloalkyl, an alkoxy, a haloalkoxy, a halo, an amino, an alkylamino, adialkylamino, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂, nitro, or an alkyl ester,wherein R₇ is defined as above and “}” represents the point ofattachment of the phenyl ring to the isoxazole ring.

In some embodiments, in the compounds represented by formulas (IV),(IVA), or (IVB), R_(g) or R_(h) is —H and the other is a substitutedphenyl represented by the following structural formula:

and

R₂₂ and R₂₃ are each, independently, an alkyl, an alkenyl, an alkynyl,cyano, a haloalkyl, an alkoxy, a haloalkoxy, a halo, an amino, analkylamino, a dialkylamino, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂, nitro, an alkylester, or hydroxyl; and R₂₁ is an alkyl, an alkenyl, an alkynyl, cyano,a haloalkyl, an alkoxy, a haloalkoxy, a halo, an amino, an alkylamino, adialkylamino, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂, nitro, or an alkyl ester,wherein R₇ is defined as above and “}” represents the point ofattachment of the phenyl ring to the isoxazole ring.

In some embodiments, in the compounds represented by formula (IA),(IIA), (IIIA), (IVA), (VA), (VIA), (VIIA), or (VIIIA), R^(x) is R^(aa),—C(O)YR^(z), or —C(O)NH—R^(aa). In one aspect, R^(x) is R^(aa). Inanother aspect, R^(x) is —C(O)YR^(z). R^(aa), R^(z), and Y are definedas for formula (IA).

In some embodiments, in the compounds represented by formula (IA),(IIA), (IIIA), (IVA), (VA), (VIA), (VIIA), or (VIIIA), R^(x) is(R^(aa))_(m). In one aspect, m is 3.

In some embodiments, in the compounds represented by formula (IA),(IIA), (IIIA), (IVA), (VA), (VIA), (VIIA), or (VIIIA), R^(x) is R^(aa)and R^(aa) is defined as for formula (IA). In one aspect, R^(aa) isglycine, serine, alanine, phenylalanine, leucine, or methionine.

In some embodiments, in the compounds represented by formula (IA),(IIA), (IIIA), (IVA), (VA), (VIA), (VIIA), or (VIIIA), R^(x) is R^(aa)and R^(aa) is a D-amino acid residue or a D-amino acid residue analog.In one aspect, R^(aa) is D-alanine, D-valine, D-leucine, D-isoleucine,D-serine, D-threonine, D-cysteine, D-methionine, D-phenylalanine,D-tyrosine, D-tryptophan, D-aspartic acid, D-asparagine, D-glutamicacid, D-glutamine, D-arginine, D-histidine, D-lysine, or D-proline.

In some embodiments, in the compounds represented by formula (IA),(IIA), (IIIA), (IVA), (VA), (VIA), (VIIA), or (VIIIA), R^(x) is R^(aa)and R^(aa) is an L-amino acid residue or an L-amino acid residue analog.In one aspect, R^(aa) is L-alanine, L-valine, L-leucine, L-isoleucine,L-serine, L-threonine, L-cysteine, L-methionine, L-phenylalanine,L-tyrosine, L-tryptophan, L-aspartic acid, L-asparagine, L-glutamicacid, L-glutamine, L-arginine, L-histidine, L-lysine, or L-proline.

In some embodiments, in the compounds represented by formula (IA),(IIA), (IIIA), (IVA), (VA), (VIA), (VIIA), or (VIIIA), R^(x) is R^(aa)and R^(y) is —H, wherein R^(aa) is defined as for formula (IA). In oneaspect, R^(aa) is glycine, alanine, valine, leucine, isoleucine, serine,threonine, cysteine, methionine, phenylalanine, tyrosine, tryptophan,aspartic acid, asparagine, glutamic acid, glutamine, arginine,histidine, lysine, or proline. In another aspect, R^(aa) is glycine,serine, alanine, phenylalanine, leucine, or methionine.

In some embodiments, in the compounds represented by formula (IA),(IIA), (IIIA), (IVA), (VA), (VIA), (VIIA), or (VIIIA), R^(x) is—C(O)YR^(z) and Y and Fr are defined as for formula (IA). In one aspect,Y is CH₂. In another aspect, Y is O. In another aspect, Y is NH. In oneaspect, R^(z) is Y₁ and Y₁ is defined as for formula (IA). In anotheraspect, R^(z) is Alk-NH₂. In another aspect, R^(z) is Alk-C(O)OH. Inanother aspect, R^(z) is Het. Alk and Het and defined as for formula(IA).

In some embodiments, in the compounds represented by formula (IA),(IIA), (IIIA), (IVA), (VA), (VIA), (VIIA), or (VIIIA), m is 1, 2 or 3.

In some embodiments, in the compounds represented by formula (IA),(IIA), (IIIA), (IVA), (VA), (VIA), (VIIA), or (VIIIA), Y₁ is PEG, HPMAcopolymer-methacryloyl-Gly-Phe-Leu-Gly-ethylenediamine, or HPMAcopolymer-methacryloyl-Gly-Phe-Leu-Gly-OH. In one aspect, Y₁ is PEG.

In some embodiments, in the compounds represented by formula (IA),(IIA), (IIIA), (IVA), (VA), (VIA), (VIIA), or (VIIIA), R^(y) is —H.

In some embodiments, in the compounds represented by formula (IA),(IIA), (IIIA), (IVA), (VA), (VIA), (VIIA), or (VIIIA), R^(y) is a loweralkyl.

In some embodiments, in the compounds represented by formula (IA),(IIA), (IIIA), (IVA), (VA), (VIA), (VIIA), or (VIIIA), Y₁ has amolecular weight greater than 20,000 daltons. In one aspect, Y₁ has amolecular weight of less than 40,000 daltons, but greater than 25,000daltons.

In some embodiments, in the compounds represented by formula (IA),(IIA), (IIIA), (IVA), (VA), (VIA), (VIIA), or (VIIIA), Alk is anoptionally substituted lower alkylene.

In some embodiments, in the compounds represented by formula (IA),(IIA), (IIIA), (IVA), (VA), (VIA), (VIIA), or (VIIIA), Het is anoptionally substituted lower heteroalkyl.

In some embodiments, in the compounds represented by formula (VA), X₁and X₂ are CH and R₁₂, R₁₃, and R₁₄ are each methoxy. In one aspect,R^(x) is R^(aa). In another aspect, R^(x) is (R^(aa))_(m). In anotheraspect, R^(x) is —R^(aa)—C(O)(CH₂)_(n)C(O)OH. In another aspect, R^(x)is —C(O)(CH₂)_(n)C(O)OH. In another aspect, R^(x) is —C(O)YR^(z). Inanother aspect, R^(x) is —C(O)NH—R^(aa). In another aspect, R^(x) is—(R″)_(q)C(O)(Y_(i)). R^(aa), Y, Rz, Y₁, m, n, and q are defined as forformula (IA).

In some embodiments, in the compounds represented by formula (VA), X₁and X₂ are CH and R₁₂, R₁₃, and R₁₄ are each methoxy. In one aspect,R^(x) is R^(aa) and R^(w) is alkoxy. In another aspect, R^(x) is R^(aa)and R^(y) is —H. In another aspect, R^(x) is R^(aa), R^(w) is alkoxy,and R^(y) is —H. In another aspect, R^(x) is R^(aa), R^(w) is alkoxy,and R^(y) is —H. In another aspect, R^(x) is R^(w) is methoxy, and R^(y)is —H. R^(aa) is defined as for formula (IA).

In some embodiments, in the compounds represented by formula (VA), X₁and X₂ are CH; R₁₂, R₁₃ and R₁₄ are methoxy; R; is —H; R^(w) is methoxy;R^(y) is —H; and R^(x) is R. R^(aa) is defined as for formula (IA).

In some embodiments, in the compounds represented by formula (VB), X₁and X₂ are CH; R₁₂, R₁₃, and R₁₄ are each methoxy; and R^(w) is alkoxy.In one aspect, R^(w) is methoxy.

In some embodiments, in the compounds represented by formula (IA or B),(IIA or B), (IIIA or B), (IVA or B), (VA or B), (VIA or B), (VIIA or B),(VIIIA or B), (IXA or B), or (XA or B), R^(w) is alkoxy. In one aspect,R^(w) is methoxy.

In some embodiments represented by formula (I), (IA), or (IB), R_(a) is—H. In some embodiments represented by formula (I), (IA), or (IB), R_(b)is —H. In some embodiments represented by formula (V), (VA), or (VB), R₁is —H. In some embodiments represented by formula (V), (VA), or (VB), R₁is —H.

In another embodiment, the invention relates to compounds selected fromthe group consisting of:

-   4-(4-Bromo-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(Naphthalen-2-yl)-5-(2-hydroxy-4-methoxy-5-ethyl-phenyl)-isoxazole;-   4-(4-Methoxy-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Iodo-phenyl)-5-(2-hydroxy-4-methoxy-5-ethyl-phenyl)-isoxazole;-   4-Phenyl-5-(2-hydroxy-4-methoxy-5-propyl-phenyl)-isoxazole;-   4-(4-Bromo-phenyl)-5-(2-hydroxy-4-methoxy-5-ethyl-phenyl)-isoxazole;-   4-(2,3-Dihydro-benzo[1,4]di-oxin-6-yl)-5-(2-hydroxy-4-methoxy-5-propyl-phenyl)-isoxazole;-   4-(4-hydroxy-phenyl)-5-(3,4,5-trihydroxy-phenyl)-isoxazole;-   4-(4-Iodo-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(3-Fluoro-4-methoxy-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Nitro-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Amino-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4′-Methoxy-biphenyl-4-yl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-[4-(pyridine-3-yl)-phenyl]-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-[4-(pyridine-4-yl)-phenyl]-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-[4-(pyridine-2-yl)-phenyl]-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(Quinolin-7-yl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(Pyridin-4-yl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(Isoquinolin-7-yl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(1-Methyl-1H-indol-5-yl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Methoxy-phenyl)-5-(benzo[1,3]dioxol-5-yl)-isoxazole;-   4-(4-Methoxy-phenyl)-5-(1-ethyl-1H-indol-6-yl)-isoxazole;-   4-(4-Carboxy-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Methoxycarbonyl-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-[4-(Oxazol-2-yl)-phenyl]-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Methoxy-phenyl)-5-(3,4,5-triethyl-phenyl)-isoxazole;-   4-(4-Iodo-phenyl)-5-(3,4,5-triethyl-phenyl)-isoxazole;-   4-(3-Fluoro-4-methoxy-phenyl)-5-(3,4,5-triethyl-phenyl)-isoxazole;-   4-(4-Nitro-phenyl)-5-(3,4,5-triethyl-phenyl)-isoxazole;-   4-(4-N,N-dimethylamino-phenyl)-5-(3,4,5-triethyl-phenyl)-isoxazole;-   4-(4-Methoxy-phenyl)-5-(3,4,5-trimethyl-phenyl)-isoxazole;-   4-[4-(Pyridin-3-yl)-phenyl]-5-(3,4,5-triethyl-phenyl)-isoxazole;-   4-[4-(Pyridin-4-yl)-phenyl]-5-(3,4,5-triethyl-phenyl)-isoxazole;-   4-[4-(Pyridin-2-yl)-phenyl]-5-(3,4,5-triethyl-phenyl)-isoxazole;-   4-(Quinolin-7-yl)-5-(3,4,5-triethyl-phenyl)-isoxazole;-   4-(Pyridin-4-yl)-5-(3,4,5-triethyl-phenyl)-isoxazole;-   4-(Isoquinolin-7-yl)-5-(3,4,5-triethyl-phenyl)-isoxazole;-   4-(1H-Indol-5-yl)-5-(3,4,5-triethyl-phenyl)-isoxazole;-   4-(4-Methoxy-phenyl)-5-(benzo[1,3]dioxol-5-yl)-isoxazole;-   4-(4-Methoxy-phenyl)-5-[1-isopropyl-1H-indol-6-yl)-isoxazole;-   4-(4-Methoxy-phenyl)-5-(2,3,4-trimethoxy-phenyl)-isoxazole;-   4-(3-Hydroxy-4-methoxy-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-[3-(Ethyl-hydroxy-phosphoryloxy)-4-methoxy-phenyl]-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Methoxy-phenyl)-5-(2-hydroxy-4-methoxy-5-ethyl-phenyl)-isoxazole;-   4-(4-Isopropyl-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Ethyl-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(5-Methoxy-pyridin-2-yl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Methoxy-phenyl)-5-(2,3,4-trimethoxy-pyridin-6-yl)-isoxazole;-   4-(4-Methoxy-phenyl)-5-(3,5-dimethoxy-4-methoxycarbonyl-phenyl)-isoxazole;-   4-(4-Methoxy-phenyl)-5-(3,5-diacetoxy-phenyl)-isoxazole;-   4-(2-Methoxy-pyridin-5-yl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Methoxy-phenyl)-5-(1-methyl-5-methoxy-1H-indol-7-yl)-isoxazole;-   4-(4-Methoxy-phenyl)-5-(1-ethyl-1H-indol-7-yl)-isoxazole;-   4-(4-Methoxy-phenyl)-5-(benzo[1,3]dioxol-4-yl)-isoxazole;-   4-(2-Hydroxy-4-methoxy-phenyl)-5-(3,4,5-trimethoxy)-isoxazole;-   4-[2-(Ethyl-hydroxy-phosphoryloxy)-4-methoxy-phenyl]-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(Pyridazin-4-yl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(Pyrimidin-5-yl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(Pyridin-3-yl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole, hydrochloric    acid salt;-   4-(3-Mercapto-4-methoxy-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(3-Phosphonosulfanyl-4-methoxy-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole,    disodium salt;-   4-(3-Acetylamino-4-methoxy-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(3-Amino-4-methoxy-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole,    hydrochloric acid salt;-   4-(2-Hydroxy-4-methoxy-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(2-Methoxy-pyridine-5-yl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(5-Methoxy-pyridine-2-yl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(3-Carboxy-4-methoxy-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole,    sodium salt;-   4-(3-Methoxycarbonyl-4-methoxy-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(3-Sulfooxy-4-methoxy-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole,    sodium salt;-   4-(2-Amino-4-methoxy-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(3,4-Dimethoxy-5-phosphonooxy-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole,    disodium salt;-   4-(2-Phosphonooxy-4-methoxy-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole,    disodium salt;-   4-(4-Methylsulfanyl-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(3-Phosphonooxy-4-methylsulfanyl-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole,    disodium salt;-   4-(3-Amino-4-methylsulfanyl-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(2,3-Dihydro-benzofuran-6-yl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Hydroxy-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole, sodium    salt;-   4-(4-Phosphonooxy-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole,    disodium salt;-   4-(4-1H-Tetrazol-5-yl-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-[4-(1-Methyl-1H-tetrazol-5-yl)-phenyl]-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(1-Methyl-1H-indol-5-yl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(Pyridazin-4-yl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole;-   4-(Pyrimidin-5-yl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole;-   4-(Pyridin-3-yl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole,    hydrochloric acid salt;-   4-(3-Mercapto-4-methoxy-phenyl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole;-   4-(3-Phosphonosulfanyl-4-methoxy-phenyl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole;-   4-(3-Acetylamino-4-methoxy-phenyl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole;-   4-(3-Amino-4-methoxy-phenyl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole,    hydrochloric acid salt;-   4-(2-Hydroxy-4-methoxy-phenyl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole;-   4-(2-Methoxy-pyridin-5-yl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole;-   4-(5-Methoxy-pyridin-2-yl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole;-   4-(3-Carboxy-4-methoxy-phenyl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole,    sodium salt;-   4-(3-Methoxycarbonyl-4-methoxy-phenyl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole;-   4-(3-Sulfooxy-4-methoxy-phenyl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole,    sodium salt;-   4-(3-Amino-4-methoxy-phenyl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole;-   4-(3,4-Dimethoxy-5-phosphonooxy-phenyl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole,    disodium salt;-   4-(2-Phosphonooxy-4-methoxy-phenyl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole,    disodium salt;-   4-(4-Methylsulfanyl-phenyl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole;-   4-(3-Phosphonooxy-4-methylsulfanyl-phenyl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole,    disodium salt;-   4-(3-Amino-4-methylsulfanyl-phenyl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole;-   4-(2,3-Dihydro-benzofuran-6-yl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole;-   4-(4-Hydroxy-phenyl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole,    sodium salt;-   4-(4-Phosphonooxy-phenyl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole;-   4-(4-1H-Tetrazol-5-yl-phenyl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole;-   4-[4-(1-Methyl-1H-tetrazol-5-yl)-phenyl]-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole;-   4-(1-Methyl-1H-indol-5-yl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole;-   4-(3,4,5-Trimethoxy-phenyl)-5-(1-methyl-1H-indol-5-yl)-isoxazole;-   4-(3,4,5-Trimethoxy-phenyl)-5-(3-phosphonooxy-4-methoxy-phenyl)-isoxazole,    disodium salt;-   4-(3,4,5-Trimethoxy-phenyl)-5-(N,N-dimethylamino-phenyl)-isoxazole;-   4-(3,4,5-Trimethoxy-phenyl)-5-(3-amino-4-methoxy-phenyl)-isoxazole,    hydrochloric acid salt;-   4-(3,4,5-Trimethoxy-phenyl)-5-[3-(3-hydroxy-2S-amino-propionamido)-4-methoxy-phenyl]-isoxazole,    hydrochloric acid salt;-   4-(4-Methoxy-phenyl)-5-(2,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Methyl-phenyl)-5-(2,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Ethoxy-phenyl)-5-(2,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Ethyl-phenyl)-5-(2,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Propoxy-phenyl)-5-(2,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Propyl-phenyl)-5-(2,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Butoxy-phenyl)-5-(2,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Butyl-phenyl)-5-(2,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Bromo-phenyl)-5-(2,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Chloro-phenyl)-5-(2,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Fluoro-phenyl)-5-(2,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Nitro-phenyl)-5-(2,4,5-trimethoxy-phenyl)-isoxazole;-   4-[4-(N,N-Dimethylamino)-phenyl]-5-(2,4,5-trimethoxy-phenyl)-isoxazole;-   4-(3,4-Dimethoxy-phenyl)-5-(2,4,5-trimethoxy-phenyl)-isoxazole;-   4-(3-Hydroxy-4-methoxy-phenyl)-5-(2,4,5-trimethoxy-phenyl)-isoxazole;-   4-(3,4,5-Trimethoxy-phenyl)-5-(2,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Methoxy-phenyl)-5-(2,3,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Methyl-phenyl)-5-(2,3,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Ethoxy-phenyl)-5-(2,3,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Ethyl-phenyl)-5-(2,3,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Propoxy-phenyl)-5-(2,3,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Propyl-phenyl)-5-(2,3,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Butoxy-phenyl)-5-(2,3,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Butyl-phenyl)-5-(2,3,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Bromo-phenyl)-5-(2,3,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Chloro-phenyl)-5-(2,3,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Fluoro-phenyl)-5-(2,3,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Nitro-phenyl)-5-(2,3,5-trimethoxy-phenyl)-isoxazole;-   4-[4-(N,N-Dimethylamino)-phenyl]-5-(2,3,5-trimethoxy-phenyl)-isoxazole;-   4-(3,4-Dimethoxy-phenyl)-5-(2,3,5-trimethoxy-phenyl)-isoxazole;-   4-(3-Hydroxy-4-methoxy-phenyl)-5-(2,3,5-trimethoxy-phenyl)-isoxazole;-   4-(3,4,5-Trimethoxy-phenyl)-5-(2,3,5-trimethoxy-phenyl)-isoxazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-5-(4-methoxy-phenyl)-isoxazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-5-(4-methyl-phenyl)-isoxazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-5-(4-ethoxy-phenyl)-isoxazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-5-(4-ethyl-phenyl)-isoxazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-5-(4-propoxy-phenyl)-isoxazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-5-(4-propyl-phenyl)-isoxazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-5-(4-butoxy-phenyl)-isoxazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-5-(4-butyl-phenyl)-isoxazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-5-(4-bromo-phenyl)-isoxazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-5-(4-chloro-phenyl)-isoxazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-5-(4-fluoro-phenyl)-isoxazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-5-(4-nitro-phenyl)-isoxazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-5-[4-(N,N,-dimethylamino)-phenyl]-isoxazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-5-(3,4-dimethoxy-phenyl)-isoxazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-5-(3-hydroxy-4-methoxy-phenyl)-isoxazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-5-(3,4-dimethoxy-phenyl)-isoxazole;-   4-(3,4-Dimethyl-phenyl)-5-(2-Hydroxy-4-methoxy-5-ethyl-phenyl)-isoxazole;-   4-(4-Chloro-phenyl)-5-(2-hydroxy-4-methoxy-5-ethyl-phenyl)-isoxazole;-   4-(4-Methyl-phenyl)-5-(2-hydroxy-4-methoxy-5-ethyl-phenyl)-isoxazole;-   4-(4-Amino-phenyl)-5-(2-hydroxy-4-methoxy-5-ethyl-phenyl)-isoxazole;-   4-(4-Trifluoromethyl-phenyl)-5-(2-hydroxy-4-methoxy-5-ethyl-phenyl)-isoxazole;-   4-(4-Methoxy-phenyl)-5-(2-hydroxy-4-methoxy-5-ethyl-phenyl)-isoxazole;-   4-(4-Bromo-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(Naphthalen-2-yl)-5-(2-hydroxy-4-methoxy-5-ethyl-phenyl)-isoxazole;-   4-(4-Methoxy-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Iodo-phenyl)-5-(2-hydroxy-4-methoxy-5-ethyl-phenyl)-isoxazole;-   4-(4-hydroxy-phenyl)-5-(3,4,5-trihydroxy-phenyl)-isoxazole;-   4-(4-Iodo-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(3-Fluoro-4-methoxy-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Nitro-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Amino-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4′-Methoxy-biphenyl-4-yl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-[4-(pyridine-3-yl)-phenyl]-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-[4-(pyridine-4-yl)-phenyl]-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-[4-(pyridine-2-yl)-phenyl]-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(Quinolin-7-yl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(Pyridin-4-yl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(Isoquinolin-7-yl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(1-Methyl-1H-indol-5-yl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Methoxy-phenyl)-5-(benzo[1,3]dioxol-5-yl)-isoxazole;-   4-(4-Methoxy-phenyl)-5-(1-ethyl-1H-indol-6-yl)-isoxazole;-   4-(4-Carboxy-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Methoxycarbonyl-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-[4-(Oxazol-2-yl)-phenyl]-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Methoxy-phenyl)-5-(3,4,5-triethyl-phenyl)-isoxazole;-   4-(4-Iodo-phenyl)-5-(3,4,5-triethyl-phenyl)-isoxazole;-   4-(3-Fluoro-4-methoxy-phenyl)-5-(3,4,5-triethyl-phenyl)-isoxazole;-   4-(4-Nitro-phenyl)-5-(3,4,5-triethyl-phenyl)-isoxazole;-   4-(4-N,N-dimethylamino-phenyl)-5-(3,4,5-triethyl-phenyl)-isoxazole;-   4-(4-Methoxy-phenyl)-5-(3,4,5-trimethyl-phenyl)-isoxazole;-   4-[4-(Pyridin-3-yl)-phenyl]-5-(3,4,5-triethyl-phenyl)-isoxazole;-   4-[4-(Pyridin-4-yl)-phenyl]-5-(3,4,5-triethyl-phenyl)-isoxazole;-   4-[4-(Pyridin-2-yl)-phenyl]-5-(3,4,5-triethyl-phenyl)-isoxazole;-   4-(Quinolin-7-yl)-5-(3,4,5-triethyl-phenyl)-isoxazole;-   4-(Pyridin-4-yl)-5-(3,4,5-triethyl-phenyl)-isoxazole;-   4-(Isoquinolin-7-yl)-5-(3,4,5-triethyl-phenyl)-isoxazole;-   4-(1H-Indol-5-yl)-5-(3,4,5-triethyl-phenyl)-isoxazole;-   4-(4-Methoxy-phenyl)-5-(benzo[1,3]dioxol-5-yl)-isoxazole;-   4-(4-Methoxy-phenyl)-5-[1-isopropyl-1H-indol-6-yl)-isoxazole;-   4-(4-Methoxy-phenyl)-5-(2,3,4-trimethoxy-phenyl)-isoxazole;-   4-(3-Hydroxy-4-methoxy-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-[3-(Ethyl-hydroxy-phosphoryloxy)-4-methoxy-phenyl]-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Isopropyl-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Ethyl-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(5-Methoxy-pyridin-2-yl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Methoxy-phenyl)-5-(2,3,4-trimethoxy-pyridin-6-yl)-isoxazole;-   4-(4-Methoxy-phenyl)-5-(3,5-Dimethoxy-4-methoxycarbonyl-phenyl)-isoxazole;-   4-(4-Methoxy-phenyl)-5-(3,5-diacetoxy-phenyl)-isoxazole;-   4-(2-Methoxy-pyridin-5-yl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Methoxy-phenyl)-5-(1-methyl-5-methoxy-1H-indol-7-yl)-isoxazole;-   4-(4-Methoxy-phenyl)-5-(1-ethyl-1H-indol-7-yl)-isoxazole;-   4-(4-Methoxy-phenyl)-5-(benzo[1,3]dioxol-4-yl)-isoxazole;-   4-(2-Hydroxy-4-methoxy-phenyl)-5-(3,4,5-trimethoxy)-isoxazole;-   4-[2-(Ethyl-hydroxy-phosphoryloxy)-4-methoxy-phenyl]-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(Pyridazin-4-yl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(Pyrimidin-5-yl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(Pyridin-3-yl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole, hydrochloric    acid salt;-   4-(3-Mercapto-4-methoxy-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(3-Phosphonosulfanyl-4-methoxy-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole,    disodium salt;-   4-(3-Acetylamino-4-methoxy-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(3-Amino-4-methoxy-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole,    hydrochloric acid salt;-   4-(2-Hydroxy-4-methoxy-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(2-Methoxy-pyridine-5-yl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(5-Methoxy-pyridine-2-yl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(3-Carboxy-4-methoxy-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole,    sodium salt;-   4-(3-Methoxycarbonyl-4-methoxy-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(3-Sulfooxy-4-methoxy-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole,    sodium salt;-   4-(2-Amino-4-methoxy-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(3,4-Dimethoxy-5-phosphonooxy-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole,    disodium salt;-   4-(2-Phosphonooxy-4-methoxy-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole,    disodium salt;-   4-(4-Methylsulfanyl-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(3-Phosphonooxy-4-methylsulfanyl-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole,    disodium salt;-   4-(3-Amino-4-methylsulfanyl-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(2,3-Dihydro-benzofuran-6-yl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Hydroxy-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole, sodium    salt;-   4-(4-Phosphonooxy-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole,    disodium salt;-   4-(4-1H-Tetrazol-5-yl-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-[4-(1-Methyl-1H-tetrazol-5-yl)-phenyl]-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(1-Methyl-1H-indol-5-yl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(Pyridazin-4-yl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole;-   4-(Pyrimidin-5-yl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole;-   4-(Pyridin-3-yl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole,    hydrochloric acid salt;-   4-(3-Mercapto-4-methoxy-phenyl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole;-   4-(3-Phosphonosulfanyl-4-methoxy-phenyl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole;-   4-(3-Acetylamino-4-methoxy-phenyl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole;-   4-(3-Amino-4-methoxy-phenyl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole,    hydrochloric acid salt;-   4-(2-Hydroxy-4-methoxy-phenyl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole;-   4-(2-Methoxy-pyridin-5-yl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole;-   4-(5-Methoxy-pyridin-2-yl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole;-   4-(3-Carboxy-4-methoxy-phenyl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole,    sodium salt;-   4-(3-Methoxycarbonyl-4-methoxy-phenyl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole;-   4-(3-Sulfooxy-4-methoxy-phenyl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole,    sodium salt;-   4-(3-Amino-4-methoxy-phenyl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole;-   4-(3,4-Dimethoxy-5-phosphonooxy-phenyl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole,    disodium salt;-   4-(2-Phosphonooxy-4-methoxy-phenyl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole,    disodium salt;-   4-(4-Methylsulfanyl-phenyl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole;-   4-(3-Phosphonooxy-4-methylsulfanyl-phenyl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole,    disodium salt;-   4-(3-Amino-4-methylsulfanyl-phenyl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole;-   4-(2,3-Dihydro-benzofuran-6-yl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole;-   4-(4-Hydroxy-phenyl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole,    sodium salt;-   4-(4-Phosphonooxy-phenyl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole;-   4-(4-1H-Tetrazol-5-yl-phenyl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole;-   4-[4-(1-Methyl-1H-tetrazol-5-yl)-phenyl]-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole;-   4-(1-Methyl-1H-indol-5-yl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole;-   4-(3,4,5-Trimethoxy-phenyl)-5-(1-methyl-1H-indol-5-yl)-isoxazole;-   4-(3,4,5-Trimethoxy-phenyl)-5-(3-phosphonooxy-4-methoxy-phenyl)-isoxazole,    disodium salt;-   4-(3,4,5-Trimethoxy-phenyl)-5-(N,N-dimethylamino-phenyl)-isoxazole;-   4-(3,4,5-Trimethoxy-phenyl)-5-(3-amino-4-methoxy-phenyl)-isoxazole,    hydrochloric acid salt;-   4-(3,4,5-Trimethoxy-phenyl)-5-[3-(3-hydroxy-2S-amino-propionamido)-4-methoxy-phenyl]-isoxazole,    hydrochloric acid salt;-   4-(4-Methoxy-phenyl)-5-(2,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Methyl-phenyl)-5-(2,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Ethoxy-phenyl)-5-(2,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Ethyl-phenyl)-5-(2,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Propoxy-phenyl)-5-(2,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Propyl-phenyl)-5-(2,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Butoxy-phenyl)-5-(2,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Butyl-phenyl)-5-(2,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Bromo-phenyl)-5-(2,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Chloro-phenyl)-5-(2,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Fluoro-phenyl)-5-(2,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Nitro-phenyl)-5-(2,4,5-trimethoxy-phenyl)-isoxazole;-   4-[4-(N,N-Dimethylamino)-phenyl]-5-(2,4,5-trimethoxy-phenyl)-isoxazole;-   4-(3,4-Dimethoxy-phenyl)-5-(2,4,5-trimethoxy-phenyl)-isoxazole;-   4-(3-Hydroxy-4-methoxy-phenyl)-5-(2,4,5-trimethoxy-phenyl)-isoxazole;-   4-(3,4,5-Trimethoxy-phenyl)-5-(2,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Methoxy-phenyl)-5-(2,3,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Methyl-phenyl)-5-(2,3,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Ethoxy-phenyl)-5-(2,3,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Ethyl-phenyl)-5-(2,3,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Propoxy-phenyl)-5-(2,3,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Propyl-phenyl)-5-(2,3,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Butoxy-phenyl)-5-(2,3,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Butyl-phenyl)-5-(2,3,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Bromo-phenyl)-5-(2,3,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Chloro-phenyl)-5-(2,3,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Fluoro-phenyl)-5-(2,3,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Nitro-phenyl)-5-(2,3,5-trimethoxy-phenyl)-isoxazole;-   4-[4-(N,N-Dimethylamino)-phenyl]-5-(2,3,5-trimethoxy-phenyl)-isoxazole;-   4-(3,4-Dimethoxy-phenyl)-5-(2,3,5-trimethoxy-phenyl)-isoxazole;-   4-(3-Hydroxy-4-methoxy-phenyl)-5-(2,3,5-trimethoxy-phenyl)-isoxazole;-   4-(3,4,5-Trimethoxy-phenyl)-5-(2,3,5-trimethoxy-phenyl)-isoxazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-5-(4-methoxy-phenyl)-isoxazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-5-(4-methyl-phenyl)-isoxazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-5-(4-ethoxy-phenyl)-isoxazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-5-(4-ethyl-phenyl)-isoxazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-5-(4-propoxy-phenyl)-isoxazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-5-(4-propyl-phenyl)-isoxazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-5-(4-butoxy-phenyl)-isoxazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-5-(4-butyl-phenyl)-isoxazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-5-(4-bromo-phenyl)-isoxazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-5-(4-chloro-phenyl)-isoxazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-5-(4-fluoro-phenyl)-isoxazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-5-(4-nitro-phenyl)-isoxazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-5-[4-(N,N,-dimethylamino)-phenyl]-isoxazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-5-(3,4-dimethoxy-phenyl)-isoxazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-5-(3-hydroxy-4-methoxy-phenyl)-isoxazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-5-(3,4-dimethoxy-phenyl)-isoxazole;-   4-(3,4-Dimethyl-phenyl)-5-(2-Hydroxy-4-methoxy-5-ethyl-phenyl)-isoxazole;-   4-(4-Chloro-phenyl)-5-(2-hydroxy-4-methoxy-5-ethyl-phenyl)-isoxazole;-   4-(4-Methyl-phenyl)-5-(2-hydroxy-4-methoxy-5-ethyl-phenyl)-isoxazole;-   4-(4-Amino-phenyl)-5-(2-hydroxy-4-methoxy-5-ethyl-phenyl)-isoxazole;    and-   4-(4-Trifluoromethyl-phenyl)-5-(2-hydroxy-4-methoxy-5-ethyl-phenyl)-isoxazole;    or

pharmaceutically acceptable salts, solvates, clathrates, or prodrugsthereof.

In another embodiment, the invention relates to compounds selected fromthe group consisting of:

-   4-(4-Bromo-phenyl)-3-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(Naphthalen-2-yl)-3-(2-hydroxy-4-methoxy-5-ethyl-phenyl)-isoxazole;-   4-(4-Methoxy-phenyl)-3-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Iodo-phenyl)-3-(2-hydroxy-4-methoxy-5-ethyl-phenyl)-isoxazole;-   4-Phenyl-3-(2-hydroxy-4-methoxy-5-propyl-phenyl)-isoxazole;-   4-(4-Bromo-phenyl)-3-(2-hydroxy-4-methoxy-5-ethyl-phenyl)-isoxazole;-   4-(2,3-Dihydro-benzo[1,4]di-oxin-6-yl)-3-(2-hydroxy-4-methoxy-5-propyl-phenyl)-isoxazole;-   4-(4-hydroxy-phenyl)-3-(3,4,5-trihydroxy-phenyl)-isoxazole;-   4-(4-Iodo-phenyl)-3-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(3-Fluoro-4-methoxy-phenyl)-3-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Nitro-phenyl)-3-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Amino-phenyl)-3-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4′-Methoxy-biphenyl-4-yl)-3-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-[4-(pyridine-3-yl)-phenyl]-3-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-[4-(pyridine-4-yl)-phenyl]-3-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-[4-(pyridine-2-yl)-phenyl]-3-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(Quinolin-7-yl)-3-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(Pyridin-4-yl)-3-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(Isoquinolin-7-yl)-3-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(1-Methyl-1H-indol-5-yl)-3-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Methoxy-phenyl)-3-(benzo[1,3]dioxol-5-yl)-isoxazole;-   4-(4-Methoxy-phenyl)-3-(1-ethyl-1H-indol-6-yl)-isoxazole;-   4-(4-Carboxy-phenyl)-3-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Methoxycarbonyl-phenyl)-3-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-[4-(Oxazol-2-yl)-phenyl]-3-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Methoxy-phenyl)-3-(3,4,5-triethyl-phenyl)-isoxazole;-   4-(4-Iodo-phenyl)-3-(3,4,5-triethyl-phenyl)-isoxazole;-   4-(3-Fluoro-4-methoxy-phenyl)-3-(3,4,5-triethyl-phenyl)-isoxazole;-   4-(4-Nitro-phenyl)-3-(3,4,5-triethyl-phenyl)-isoxazole;-   4-(4-N,N-dimethylamino-phenyl)-3-(3,4,5-triethyl-phenyl)-isoxazole;-   4-(4-Methoxy-phenyl)-3-(3,4,5-trimethyl-phenyl)-isoxazole;-   4-[4-(Pyridin-3-yl)-phenyl]-3-(3,4,5-triethyl-phenyl)-isoxazole;-   4-[4-(Pyridin-4-yl)-phenyl]-3-(3,4,5-triethyl-phenyl)-isoxazole;-   4-[4-(Pyridin-2-yl)-phenyl]-3-(3,4,5-triethyl-phenyl)-isoxazole;-   4-(Quinolin-7-yl)-3-(3,4,5-triethyl-phenyl)-isoxazole;-   4-(Pyridin-4-yl)-3-(3,4,5-triethyl-phenyl)-isoxazole;-   4-(Isoquinolin-7-yl)-3-(3,4,5-triethyl-phenyl)-isoxazole;-   4-(1H-Indol-5-yl)-3-(3,4,5-triethyl-phenyl)-isoxazole;-   4-(4-Methoxy-phenyl)-3-(benzo[1,3]dioxol-5-yl)-isoxazole;-   4-(4-Methoxy-phenyl)-3-[1-isopropyl-1H-indol-6-yl)-isoxazole;-   4-(4-Methoxy-phenyl)-3-(2,3,4-trimethoxy-phenyl)-isoxazole;-   4-(3-Hydroxy-4-methoxy-phenyl)-3-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-[3-(Ethyl-hydroxy-phosphoryloxy)-4-methoxy-phenyl]-3-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Methoxy-phenyl)-3-(2-hydroxy-4-methoxy-5-ethyl-phenyl)-isoxazole;-   4-(4-Isopropyl-phenyl)-3-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-3-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Ethyl-phenyl)-3-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(5-Methoxy-pyridin-2-yl)-3-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Methoxy-phenyl)-3-(2,3,4-trimethoxy-pyridin-6-yl)-isoxazole;-   4-(4-Methoxy-phenyl)-3-(3,5-Dimethoxy-4-methoxycarbonyl-phenyl)-isoxazole;-   4-(4-Methoxy-phenyl)-3-(3,5-diacetoxy-phenyl)-isoxazole;-   4-(2-Methoxy-pyridin-5-yl)-3-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Methoxy-phenyl)-3-(1-methyl-5-methoxy-1H-indol-7-yl)-isoxazole;-   4-(4-Methoxy-phenyl)-3-(1-ethyl-1H-indol-7-yl)-isoxazole;-   4-(4-Methoxy-phenyl)-3-(benzo[1,3]dioxol-4-yl)-isoxazole;-   4-(2-Hydroxy-4-methoxy-phenyl)-3-(3,4,5-trimethoxy)-isoxazole;-   4-[2-(Ethyl-hydroxy-phosphoryloxy)-4-methoxy-phenyl]-3-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(Pyridazin-4-yl)-3-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(Pyrimidin-5-yl)-3-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(Pyridin-3-yl)-3-(3,4,5-trimethoxy-phenyl)-isoxazole, hydrochloric    acid salt;-   4-(3-Mercapto-4-methoxy-phenyl)-3-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(3-Phosphonosulfanyl-4-methoxy-phenyl)-3-(3,4,5-trimethoxy-phenyl)-isoxazole,    disodium salt;-   4-(3-Acetylamino-4-methoxy-phenyl)-3-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(3-Amino-4-methoxy-phenyl)-3-(3,4,5-trimethoxy-phenyl)-isoxazole,    hydrochloric acid salt;-   4-(2-Hydroxy-4-methoxy-phenyl)-3-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(2-Methoxy-pyridine-5-yl)-3-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(5-Methoxy-pyridine-2-yl)-3-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(3-Carboxy-4-methoxy-phenyl)-3-(3,4,5-trimethoxy-phenyl)-isoxazole,    sodium salt;-   4-(3-Methoxycarbonyl-4-methoxy-phenyl)-3-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(3-Sulfooxy-4-methoxy-phenyl)-3-(3,4,5-trimethoxy-phenyl)-isoxazole,    sodium salt;-   4-(2-Amino-4-methoxy-phenyl)-3-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(3,4-Dimethoxy-5-phosphonooxy-phenyl)-3-(3,4,5-trimethoxy-phenyl)-isoxazole,    disodium salt;-   4-(2-Phosphonooxy-4-methoxy-phenyl)-3-(3,4,5-trimethoxy-phenyl)-isoxazole,    disodium salt;-   4-(4-Methylsulfanyl-phenyl)-3-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(3-Phosphonooxy-4-methylsulfanyl-phenyl)-3-(3,4,5-trimethoxy-phenyl)-isoxazole,    disodium salt;-   4-(3-Amino-4-methylsulfanyl-phenyl)-3-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(2,3-Dihydro-benzofuran-6-yl)-3-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Hydroxy-phenyl)-3-(3,4,5-trimethoxy-phenyl)-isoxazole, sodium    salt;-   4-(4-Phosphonooxy-phenyl)-3-(3,4,5-trimethoxy-phenyl)-isoxazole,    disodium salt;-   4-(4-1H-Tetrazol-5-yl-phenyl)-3-(3,4,5-trimethoxy-phenyl)-isoxazole

4-[4-(1-Methyl-1H-tetrazol-5-yl)-phenyl]-3-(3,4,5-trimethoxy-phenyl)-isoxazole;

-   4-(1-Methyl-1H-indol-5-yl)-3-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(Pyridazin-4-yl)-3-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole;-   4-(Pyrimidin-5-yl)-3-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole;-   4-(Pyridin-3-yl)-3-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole,    hydrochloric acid salt;-   4-(3-Mercapto-4-methoxy-phenyl)-3-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole;-   4-(3-Phosphonosulfanyl-4-methoxy-phenyl)-3-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole;-   4-(3-Acetylamino-4-methoxy-phenyl)-3-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole;-   4-(3-Amino-4-methoxy-phenyl)-3-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole,    hydrochloric acid salt;-   4-(2-Hydroxy-4-methoxy-phenyl)-3-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole;-   4-(2-Methoxy-pyridin-5-yl)-3-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole;-   4-(5-Methoxy-pyridin-2-yl)-3-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole;-   4-(3-Carboxy-4-methoxy-phenyl)-3-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole,    sodium salt;-   4-(3-Methoxycarbonyl-4-methoxy-phenyl)-3-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole;-   4-(3-Sulfooxy-4-methoxy-phenyl)-3-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole,    sodium salt;-   4-(3-Amino-4-methoxy-phenyl)-3-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole;-   4-(3,4-Dimethoxy-5-phosphonooxy-phenyl)-3-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole,    disodium salt;-   4-(2-Phosphonooxy-4-methoxy-phenyl)-3-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole,    disodium salt;-   4-(4-Methylsulfanyl-phenyl)-3-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole;-   4-(3-Phosphonooxy-4-methylsulfanyl-phenyl)-3-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole,    disodium salt;-   4-(3-Amino-4-methylsulfanyl-phenyl)-3-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole;-   4-(2,3-Dihydro-benzofuran-6-yl)-3-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole;-   4-(4-Hydroxy-phenyl)-3-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole,    sodium salt;-   4-(4-Phosphonooxy-phenyl)-3-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole;-   4-(4-1H-Tetrazol-5-yl-phenyl)-3-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole;-   4-[4-(1-Methyl-1H-tetrazol-5-yl)-phenyl]-3-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole;-   4-(1-Methyl-1H-indol-5-yl)-3-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole;-   4-(3,4,5-Trimethoxy-phenyl)-3-(1-methyl-1H-indol-5-yl)-isoxazole;-   4-(3,4,5-Trimethoxy-phenyl)-3-(3-phosphonooxy-4-methoxy-phenyl)-isoxazole,    disodium salt;-   4-(3,4,5-Trimethoxy-phenyl)-3-(N,N-dimethylamino-phenyl)-isoxazole;-   4-(3,4,5-Trimethoxy-phenyl)-3-(3-amino-4-methoxy-phenyl)-isoxazole,    hydrochloric acid salt;-   4-(3,4,5-Trimethoxy-phenyl)-3-[3-(3-hydroxy-2S-amino-propionamido)-4-methoxy-phenyl]-isoxazole,    hydrochloric acid salt;-   4-(4-Methoxy-phenyl)-3-(2,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Methyl-phenyl)-3-(2,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Ethoxy-phenyl)-3-(2,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Ethyl-phenyl)-3-(2,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Propoxy-phenyl)-3-(2,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Propyl-phenyl)-3-(2,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Butoxy-phenyl)-3-(2,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Butyl-phenyl)-3-(2,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Bromo-phenyl)-3-(2,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Chloro-phenyl)-3-(2,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Fluoro-phenyl)-3-(2,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Nitro-phenyl)-3-(2,4,5-trimethoxy-phenyl)-isoxazole;-   4-[4-(N,N-Dimethylamino)-phenyl]-3-(2,4,5-trimethoxy-phenyl)-isoxazole;-   4-(3,4-Dimethoxy-phenyl)-3-(2,4,5-trimethoxy-phenyl)-isoxazole;-   4-(3-Hydroxy-4-methoxy-phenyl)-3-(2,4,5-trimethoxy-phenyl)-isoxazole;-   4-(3,4,5-Trimethoxy-phenyl)-3-(2,4,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Methoxy-phenyl)-3-(2,3,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Methyl-phenyl)-3-(2,3,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Ethoxy-phenyl)-3-(2,3,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Ethyl-phenyl)-3-(2,3,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Propoxy-phenyl)-3-(2,3,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Propyl-phenyl)-3-(2,3,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Butoxy-phenyl)-3-(2,3,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Butyl-phenyl)-3-(2,3,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Bromo-phenyl)-3-(2,3,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Chloro-phenyl)-3-(2,3,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Fluoro-phenyl)-3-(2,3,5-trimethoxy-phenyl)-isoxazole;-   4-(4-Nitro-phenyl)-3-(2,3,5-trimethoxy-phenyl)-isoxazole;-   4-[4-(N,N-Dimethylamino)-phenyl]-3-(2,3,5-trimethoxy-phenyl)-isoxazole;-   4-(3,4-Dimethoxy-phenyl)-3-(2,3,5-trimethoxy-phenyl)-isoxazole;-   4-(3-Hydroxy-4-methoxy-phenyl)-3-(2,3,5-trimethoxy-phenyl)-isoxazole;-   4-(3,4,5-Trimethoxy-phenyl)-3-(2,3,5-trimethoxy-phenyl)-isoxazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-3-(4-methoxy-phenyl)-isoxazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-3-(4-methyl-phenyl)-isoxazole

4-(2,3,4,5-Tetramethoxy-phenyl)-3-(4-ethoxy-phenyl)-isoxazole;

-   4-(2,3,4,5-Tetramethoxy-phenyl)-3-(4-ethyl-phenyl)-isoxazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-3-(4-propoxy-phenyl)-isoxazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-3-(4-propyl-phenyl)-isoxazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-3-(4-butoxy-phenyl)-isoxazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-3-(4-butyl-phenyl)-isoxazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-3-(4-bromo-phenyl)-isoxazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-3-(4-chloro-phenyl)-isoxazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-3-(4-fluoro-phenyl)-isoxazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-3-(4-nitro-phenyl)-isoxazole

4-(2,3,4,5-Tetramethoxy-phenyl)-3-[4-(N,N,-dimethylamino)-phenyl]-isoxazole;

-   4-(2,3,4,5-Tetramethoxy-phenyl)-3-(3,4-dimethoxy-phenyl)-isoxazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-3-(3-hydroxy-4-methoxy-phenyl)-isoxazole;-   4-(2,3,4,5-Tetramethoxy-phenyl)-3-(3,4,5-trimethoxy-phenyl)-isoxazole;-   4-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-3-(3,4-dimethoxy-phenyl)-isoxazole;-   4-(3,4-Dimethyl-phenyl)-3-(2-hydroxy-4-methoxy-5-ethyl-phenyl)-isoxazole;-   4-(4-Chloro-phenyl)-3-(2-hydroxy-4-methoxy-5-ethyl-phenyl)-isoxazole;-   4-(4-Methyl-phenyl)-3-(2-hydroxy-4-methoxy-5-ethyl-phenyl)-isoxazole;-   4-(4-Amino-phenyl)-3-(2-hydroxy-4-methoxy-5-ethyl-phenyl)-isoxazole;-   4-(4-Trifluoromethyl-phenyl)-3-(2-hydroxy-4-methoxy-5-ethyl-phenyl)-isoxazole;-   4-(4-Methoxy-phenyl)-3-(2-hydroxy-4-methoxy-5-ethyl-phenyl)-isoxazole;    and-   4-(3,4,5-Trimethoxy-phenyl)-3-(4-bromo-phenyl)-isoxazole; or

pharmaceutically acceptable salts, solvates, clathrates, or prodrugsthereof.

In another embodiment, the invention relates to compounds selected fromthe group consisting of:

-   2-amino-N-(2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl)-phenyl)acetamide    hydrochloride;-   2-amino-3-hydroxy-N-(2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl)-phenyl)propanamide    hydrochloride;-   2-amino-N-(2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl)-phenyl)propanamide;-   2-amino-N-(2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl)-phenyl)-4-(methylthio)butanamide    hydrochloride;-   2-amino-N-(2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl)-phenyl)butanamide;-   2-amino-N-(2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl)-phenyl)-3-phenylpropanamide    hydrochloride;-   2-amino-N-(2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl)-phenyl)-4-methylpentanamide    hydrochloride;-   2-amino-N-(2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl)-phenyl)-3-(4-methoxyphenyl)propanamide    hydrochloride;-   1-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl]-phenylcarbonnoyl}-2-methyl-propyl-ammonium    chloride;-   1-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl]-phenylcarbomoyl}-2-methyl-butyl-ammonium    chloride;-   2-hydroxy-1-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl]-phenylcarbonnoyl}-propyl-ammonium    chloride;-   2-(4-hydroxy-phenyl)-1-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl]-phenylcarbonnoyl}-ethyl-ammonium    chloride;-   C-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl]-phenylcarbonnoyl}-C-phenyl-methyl-ammonium    chloride;-   2-(1H-indol-2-yl)-1-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl]-phenylcarbonnoyl}-ethyl-ammonium    chloride;-   2-benzofuran-2-yl-1-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl]-phenylcarbonnoyl}-ethyl-ammonium    chloride;-   2-carboxyl-1-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl]-phenylcarbonnoyl}-ethyl-ammonium    chloride;-   3-carboxyl-1-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl]-phenylcarbonnoyl}-propyl-ammonium    chloride;-   3-carbamoyl-1-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl]-phenylcarbomoyl}-propyl-ammonium    chloride;-   2-carbamoyl-1-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl]-phenylcarbomoyl}-ethyl-ammonium    chloride;-   2-(3H-imidazol-4-yl)-1-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl]-phenylcarbomoyl}-ethyl-ammonium    chloride;-   5-amino-1-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl]-phenylcarbomoyl}-pentyl-ammonium    chloride;-   4-guanidino-1-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl]-phenylcarbomoyl}-butyl-ammonium    chloride;-   N-[2-methoxy-5-{5-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl]-phenyl}succinamic    acid;-   4-[2-methoxy-5-{5-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl]-phenylcarbamoyl}-butyric    acid;-   2-[2-methoxy-5-{5-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl]-phenylcarbamoylyethyl-ammonium    chloride;-   3-(2-methoxy-ethoxy)-N-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl]-phenyl}-propionamide;-   3-(2-PEG)-N-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl]-phenyl}-propionamide;-   N-[2-methoxy-5-{5-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl]-phenyl}-3-(2-methylamino-ethylamino)-propionamide;-   3-PEG-N-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl]-phenylcarbamoyl}-methyl)-propionamide;-   N-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl]-phenylcarbamoyl}-methyl)-succinamic    acid-   {2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl]-phenyl}-carbamic    acid 2-methoxy-ethyl ester;-   2-methoxy-5-(5-(3,4,5-trimethoxyphenyl)isoxazol-4-yl)    phenylcarbamate-PEG;-   3-amino-N-[4-guanadino-1-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl]-phenylcarbamoyl}-butylcarbamoyl)-methyl]-succinamic    acid;-   3-amino-N-[4-guanadino-1-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl]-phenylcarbamoyl}-butylcarbamoyl)-methyl]-succinamic    acid;-   2-amino-N-(2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl)-phenyl)propanamide    hydrochloride;-   2-amino-N-(2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl)-phenyl)    acetamide hydrochloride;-   2-amino-3-hydroxy-N-(2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl)-phenyl)propanamide    hydrochloride;-   2-amino-N-(2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl)-phenyl)propanamide;-   2-amino-N-(2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl)-phenyl)-4-(methylthio)butanamide    hydrochloride;-   2-amino-N-(2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl)-phenyl)butanamide;-   2-amino-N-(2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl)-phenyl)-3-phenylpropanamide    hydrochloride;-   2-amino-N-(2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl)-phenyl)-4-methylpentanamide    hydrochloride;-   2-amino-N-(2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl)-phenyl)-3-(4-methoxyphenyl)propanamide    hydrochloride;-   1-[2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl]-phenylcarbonnoyl}-2-methyl-propyl-ammonium    chloride;-   1-[2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl]-phenylcarbonnoyl}-2-methyl-butyl-ammonium    chloride;-   2-hydroxy-1-[2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl]-phenylcarbonnoyl}-propyl-ammonium    chloride;-   2-(4-hydroxy-phenyl)-1-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl]-phenylcarbonnoyl}-ethyl-ammonium    chloride;-   C-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl]-phenylcarbonnoyl}-C-phenyl-methyl-ammonium    chloride;-   2-(1H-indol-2-yl)-1-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl]-phenylcarbonnoyl}-ethyl-ammonium    chloride;-   2-benzofuran-2-yl-1-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl]-phenylcarbonnoyl}-ethyl-ammonium    chloride;-   2-carboxyl-1-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl]-phenylcarbonnoyl}-ethyl-ammonium    chloride;-   3-carboxyl-1-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl]-phenylcarbonnoyl}-propyl-ammonium    chloride;-   3-carboxyl-1-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl]-phenylcarbomoyl}-propyl-ammonium    chloride;

3-carbamoyl-1-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl]-phenylcarbonnoyl}-propyl-ammoniumchloride;

-   2-carbamoyl-1-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl]-phenylcarbomoylyethyl-ammonium    chloride;-   2-(3H-imidazol-4-yl)-1-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl]phenylcarbomoyl}-ethyl-ammonium    chloride;-   5-amino-1-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl]-phenylcarbonnoyl}-pentyl-ammonium    chloride;-   4-guanidino-1-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl]-phenylcarbonnoyl}-butyl-ammonium    chloride;-   N-[2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl]-phenyl)    succinamic acid;-   4-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl]-phenylcarbamoyl}-butyric    acid;-   2-[2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl]-phenylcarbamoylyethyl-ammonium    chloride;-   3-(2-methoxy-ethoxy)-N-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl]-phenyl}-propionamide;-   3-(2-PEG)-N-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl]-phenyl}-propionamide;-   N-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl]-phenyl}-3-(2-methylamino-ethylamino)-propionamide;-   3-PEG-N-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl]-phenylcarbamoyl}-methyl)-propionamide;-   N-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl]-phenylcarbamoyl}-methyl)-succinamic    acid;-   {2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl]-phenyl}-carbamic    acid 2-methoxy-ethyl ester;-   2-methoxy-5-(3-(3,4,5-trimethoxyphenyl)isoxazol-4-yl)phenylcarbamate-PEG;-   3-amino-N-[4-guanadino-1-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl]-phenylcarbamoyl}-butylcarbamoyl)-methyl]-succinamic    acid;-   3-amino-N-[4-guanadino-1-{2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl]-phenylcarbamoyl}-butylcarbamoyl)-methyl]-succinamic    acid;-   2-amino-N-(2-methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl)-phenyl)propanamide    hydrochloride;-   methyl-2-(2-(2-methoxy-5-(5-(3,4,5-trimethoxyphenyl)isoxazol-4-yl)phenylamino)-2-oxoethylamino)acetate;-   4-amino-5-(2-methoxy-5-(5-(3,4,5-trimethoxyphenyl)isoxazol-4-yl)phenylamino)-5-oxopentanoic    acid hydrochloride;-   3-amino-N-(2-methoxy-5-(5-(3,4,5-trimethoxyphenyl)isoxazol-4-yl)phenyl)propanamide    hydrochloride;-   3-amino-N-(2-methoxy-5-(5-(3,4,5-trimethoxyphenyl)isoxazol-4-yl)phenyl)-4-methylpentanamide    hydrochloride;-   methyl-2-(2-(2-methoxy-5-(3-(3,4,5-trimethoxyphenyl)isoxazol-4-yl)phenylamino)-2-oxoethylamino)acetate;-   4-amino-5-(2-methoxy-5-(3-(3,4,5-trimethoxyphenyl)isoxazol-4-yl)phenylamino)-5-oxopentanoic    acid hydrochloride;-   3-amino-N-(2-methoxy-5-(3-(3,4,5-trimethoxyphenyl)isoxazol-4-yl)phenyl)propanamide    hydrochloride; and-   3-amino-N-(2-methoxy-5-(3-(3,4,5-trimethoxyphenyl)isoxazol-4-yl)phenyl)-4-methylpentanamide    hydrochloride; or

a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof.

All of the features, specific embodiments and particular substituentsdisclosed herein may be combined in any combination. Each feature,embodiment or substituent disclosed in this specification may bereplaced by an alternative feature, embodiment or substituent servingthe same, equivalent, or similar purpose. In the case of chemicalcompounds, specific values for variables (e.g., values shown in theexemplary compounds disclosed herein) in any chemical formula disclosedherein can be combined in any combination resulting in a stablestructure. Furthermore, specific values (whether preferred or not) forsubstituents in one type of chemical structure may be combined withvalues for other substituents (whether preferred or not) in the same ordifferent type of chemical structure. Thus, unless expressly statedotherwise, each feature, embodiment or substituent disclosed is only anexample of a generic series of equivalent or similar features,embodiments or substituents.

In another embodiment, the invention relates to pharmaceuticalcompositions that comprise a compound of any one of formulas (I) through(X), (IA) through (XA), (IB) through (XB), or of Table 1, or apharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, as an active ingredient, and a pharmaceutically acceptablecarrier or vehicle. The compositions are useful for treating orpreventing proliferative disorders such as cancer or maculardegeneration.

In another embodiment, the invention relates to methods for inhibitingtubulin polymerization in a cell comprising contacting the cell with aneffective amount of a compound represented by any one of formulas (I)through (X), (IA) through (XA), (IB) through (XB), or of Table 1, or apharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof.

In another embodiment, the invention relates to methods for promotingmicrotubule depolymerization in a cell comprising contacting the cellwith an effective amount of a compound represented by any one offormulas (I) through (X), (IA) through (XA), (IB) through (XB), or ofTable 1, or a pharmaceutically acceptable salt, solvate, clathrate, orprodrug thereof.

In another embodiment, the invention relates to methods for promotingmicrotubule depolymerization in a subject comprising administering tothe subject an effective amount of a compound represented by any one offormulas (I) through (X), (IA) through (XA), (IB) through (XB), or ofTable 1, or a pharmaceutically acceptable salt, solvate, clathrate, orprodrug thereof.

In another embodiment, the invention relates to methods for treating orpreventing a proliferative disorder in a subject in need thereofcomprising administering an effective amount of a compound representedby any one of formulas (I) through (X), (IA) through (XA), (IB) through(XB), or of Table 1, or a pharmaceutically acceptable salt, solvate,clathrate, or prodrug thereof.

In another embodiment, the invention relates to methods for treatingcancer in a subject in need thereof comprising administering aneffective amount of a compound represented by any one of formulas (I)through (X), (IA) through (XA), (IB) through (XB), or of Table 1, or apharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof. In one aspect of this embodiment, the method involves treatinga subject with multidrug resistant cancer. In another aspect of thisembodiment, the method involves treating a subject having a solid tumor.In another aspect of this embodiment, the method involves treating asubject having a hematological malignancy.

In another embodiment, the invention relates to methods for treatingcancer in a subject in need thereof comprising administering aneffective amount of a compound represented by any one of formulas (I)through (X), (IA) through (XA), (IB) through (XB), or of Table 1, or apharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, and an additional therapeutic agent. In one aspect of thisembodiment, the additional therapeutic agent is another anti-canceragent.

In another embodiment, the invention relates to methods for blocking,occluding, or otherwise disrupting blood flow in neovasculature,comprising contacting the neovasculature with an effective amount of acompound represented by any one of formulas (I) through (X), (IA)through (XA), (IB) through (XB), or of Table 1, or a pharmaceuticallyacceptable salt, solvate, clathrate, or prodrug thereof, and anadditional therapeutic agent.

In another embodiment, the invention relates to methods blocking,occluding, or otherwise disrupting blood flow in neovasculature in asubject, comprising administering to the subject an effective amount ofa compound represented by any one of formulas (I) through (X), (IA)through (XA), (IB) through (XB), or of Table 1, or a pharmaceuticallyacceptable salt, solvate, clathrate, or prodrug thereof, and anadditional therapeutic agent.

Exemplary Compounds of the Invention

Exemplary compounds of the invention are depicted in Table 1 below.

TABLE 1 Compound No. Structure Chemical Name  1

4-(4-Bromo-phenyl)-5- (3,4,5-trimethoxy-phenyl)- isoxazole  2

4-(4-Bromo-phenyl)-5- (3,4,5-trimethoxy-phenyl)- isoxazole  3

4-(4-Methoxy-phenyl)-5- (3,4,5-trimethoxy-phenyl)- isoxazole  4

4-(4-Iodo-phenyl)-5-(2- hydroxy-4-methoxy-5- ethyl-phenyl)-isoxazole  5

4-Phenyl-5-(2-hydroxy-4- methoxy-5-propyl-phenyl)- isoxazole  6

4-(4-Bromo-phenyl)-5-(2- hydroxy-4-methoxy-5-ethyl- phenyl)-isoxazole  7

4-(2,3-Dihydro- benzo[1,4]di-oxin-6-yl)-5- (2-hydroxy-4-methoxy-5-propyl-phenyl)-isoxazole  8

4-(4-hydroxy-phenyl)-5- (3,4,5-trihydroxy-phenyl)- isoxazole  9

4-(4-Iodo-phenyl)-5- (3,4,5-trimethoxy-phenyl)- isoxazole  10

4-(3-Fluoro-4-methoxy- phenyl)-5-(3,4,5-trimethoxy- phenyl)-isoxazole 11

4-(4-Nitro-phenyl)-5- (3,4,5-trimethoxy-phenyl)- isoxazole  12

4-(4-Amino-phenyl)-5- (3,4,5-trimethoxy-phenyl)- isoxazole  13

4-(4′-Methoxy-biphenyl-4- yl)-5-(3,4,5-trimethoxy- phenyl)-isoxazole  14

4-[4-(pyridine-3-yl)-phenyl]- 5-(3,4,5-trimethoxy-phenyl)- isoxazole  15

4-[4-(pyridine-4-yl)-phenyl]- 5-(3,4,5-trimethoxy-phenyl)- isoxazole  16

4-[4-(pyridine-2-yl)-phenyl]- 5-(3,4,5-trimethoxy-phenyl)- isoxazole  17

4-(Quinolin-7-yl)-5- (3,4,5-trimethoxy-phenyl)- isoxazole  18

4-(Pyridin-4-yl)-5- (3,4,5-trimethoxy-phenyl)- isoxazole  19

4-(Isoquinolin-7-yl)-5- (3,4,5-trimethoxy-phenyl)- isoxazole  20

4-(1-Methyl-1H-indol-5-yl)- 5-(3,4,5-trimethoxy-phenyl)- isoxazole  21

4-(4-Methoxy-phenyl)-5- (benzo[1,3]dioxol-5-yl)- isoxazole  22

4-(4-Methoxy-phenyl)-5- (1-ethyl-1H-indol-6-yl)- isoxazole  23

4-(4-Carboxy-phenyl)-5- (3,4,5-trimethoxy-phenyl)- isoxazole  24

4-(4-Methoxycarbonyl- phenyl)-5-(3,4,5-trimethoxy- phenyl)-isoxazole  25

4-[4-(Oxazol-2-yl)-phenyl]- 5-(3,4,5-trimethoxy-phenyl)- isoxazole  26

4-(4-Methoxy-phenyl)-5- (3,4,5-triethyl-phenyl)- isoxazole  27

4-(4-Iodo-phenyl)-5- (3,4,5-triethyl-phenyl)- isoxazole  28

4-(3-Fluoro-4-methoxy- phenyl)-5-(3,4,5-triethyl- phenyl)-isoxazole  29

4-(4-Nitro-phenyl)-5- (3,4,5-triethyl-phenyl)- isoxazole  30

4-(4-N,N-dimethylamino- phenyl)-5-(3,4,5-triethyl- isoxazole  31

4-(4-Methoxy-phenyl)-5- (3,4,5-trimethyl-phenyl)- isoxazole  32

4-[4-(Pyridin-3-yl)-phenyl]- 5-(3,4,5-triethyl-phenyl)- isoxazole  33

4-[4-(Pyridin-4-yl)-phenyl]- 5-(3,4,5-triethyl-phenyl)- isoxazole  34

4-[4-(Pyridin-2-yl)-phenyl]- 5-(3,4,5-triethyl-phenyl)- isoxazole  35

4-(Quinolin-7-yl)-5- (3,4,5-triethyl-phenyl)- isoxazole  36

4-(Pyridin-4-yl)-5-(3,4,5- triethyl-phenyl)-isoxazole  37

4-(Isoquinolin-7-yl)-5- (3,4,5-triethyl-phenyl)- isoxazole  38

4-(1H-Indol-5-yl)-5- (3,4,5-triethyl-phenyl)- isoxazole  39

4-(4-Methoxy-phenyl)-5- (benzo[1,3]dioxol-5-yl)- isoxazole  40

4-(4-Methoxy-phenyl)-5- [1-isopropyl-1H-indol-6- yl)-isoxazole  41

4-(4-Methoxy-phenyl)-5- (2,3,4-trimethoxy-phenyl)- isoxazole  42

4-(3-Hydroxy-4-methoxy- phenyl)-5-(3,4,5-trimethoxy- phenyl)-isoxazole 43

4-[3-(Ethyl-hydroxy- phosphoryloxy)-4-methoxy-phenyl]-5-(3,4,5-trimethoxy- phenyl)-isoxazole  44

4-(4-Methoxy-phenyl)-5-(2- hydroxy-4-methoxy-5-ethyl- phenyl)-isoxazole; 45

4-(4-Isopropyl-phenyl)-5- (3,4,5-trimethoxy-phenyl)- isoxazole  46

4-(2,3-Dihydro- benzo[1,4]dioxin-6-yl)-5- (3,4,5-trimethoxy-phenyl)-isoxazole  47

4-(4-Ethyl-phenyl)-5- (3,4,5-trimethoxy-phenyl)- isoxazole  48

4-(5-Methoxy-pyridin-2-yl)- 5-(3,4,5-trimethoxy-phenyl)- isoxazole  49

4-(4-Methoxy-phenyl)-5- (2,3,4-trimethoxy-pyridin- 6-yl)-isoxazole  50

4-(4-Methoxy-phenyl)-5- (3,5-dimethoxy-4- methoxycarbonyl-phenyl)-isoxazole  51

4-(4-Methoxy-phenyl)-5- (3,5-diacetoxy-phenyl)- isoxazole  52

4-(2-Methoxy-pyridin-5-yl)- 5-(3,4,5-trimethoxy-phenyl)- isoxazole  53

4-(4-Methoxy-phenyl)-5- (1-methyl-5-methoxy- 1H-indol-7-yl)-isoxazole 54

4-(4-Methoxy-phenyl)-5- (1-ethyl-1H-indol-7-yl)- isoxazole  55

4-(4-Methoxy-phenyl)-5- (benzo[1,3]dioxol-4-yl)- isoxazole  56

4-(2-Hydroxy-4-methoxy- phenyl)-5-(3,4,5- trimethoxy)-isoxazole  57

4-[2-(Ethyl-hydroxy- phosphoryloxy)-4-methoxy-phenyl]-5-(3,4,5-trimethoxy- phenyl)-isoxazole  58

4-(Pyridazin-4-yl)-5-(3,4,5- trimethoxy-phenyl)- isoxazole  59

4-(Pyrimidin-5-yl)-5-(3,4,5- trimethoxy-phenyl)- isoxazole  60

4-(Pyridin-3-yl)-5-(3,4,5- trimethoxy-phenyl)- isoxazole, hydrochloricacid salt  61

4-(3-Mercapto-4-methoxy- phenyl)-5-(3,4,5-trimethoxy- phenyl)-isoxazole 62

4-(3-Phosphonosulfanyl-4- methoxy-phenyl)-5-(3,4,5- trimethoxy-phenyl)-isoxazole, disodium salt  63

4-(3-Acetylamino-4- methoxy-phenyl)-5-(3,4,5- trimethoxy-phenyl)-isoxazole  64

2-methoxy-5-[5-(3,4,5- trimethoxy-phenyl)- isoxazol-4-yl)-phenylaminehydrochloride  65

4-(2-Hydroxy-4-methoxy- phenyl)-5-(3,4,5-trimethoxy- phenyl)-isoxazole 66

4-(2-Methoxy-pyridine-5- yl)-5-(3,4,5-trimethoxy- phenyl)-isoxazole  67

4-(5-Methoxy-pyridine-2- yl)-5-(3,4,5-trimethoxy- phenyl)-isoxazole  68

4-(3-Carboxy-4-methoxy- phenyl)-5-(3,4,5-trimethoxy- phenyl)-isoxazole,sodium salt  69

4-(3-Methoxycarbonyl-4- methoxy-phenyl)-5-(3,4,5- trimethoxy-phenyl)-isoxazole  70

4-(3-Sulfooxy-4-methoxy- phenyl)-5-(3,4,5-trimethoxy- phenyl)-isoxazole,sodium salt  71

4-(2-Amino-4-methoxy- phenyl)-5-(3,4,5-trimethoxy- phenyl)-isoxazole  72

4-(3,4-Dimethoxy-5- phosphonooxy-phenyl)-5- (3,4,5-trimethoxy-phenyl)-isoxazole, disodium salt  73

4-(2-Phosphonooxy-4- methoxy-phenyl)-5-(3,4,5- trimethoxy-phenyl)-isoxazole,disodium salt  74

4-(4-Methylsulfanyl-phenyl)-5-(3,4,5-trimethoxy- phenyl)-isoxazole  75

4-(3-Phosphonooxy-4- methylsulfanyl-phenyl)-5-(3,4,5-trimethoxy-phenyl)- isoxazole, disodium salt  76

4-(3-Amino-4- methylsulfanyl-phenyl)-5- (3,4,5-trimethoxy-phenyl)-isoxazole  77

4-(2,3-Dihydro-benzofuran- 6-yl)-5-(3,4,5-trimethoxy- phenyl)-isoxazole 78

4-(4-Hydroxy-phenyl)-5- (3,4,5-trimethoxy-phenyl)- isoxazole, sodiumsalt  79

4-(4-Phosphonooxy-phenyl)- 5-(3,4,5-trimethoxy-phenyl)- isoxazole,disodium salt  80

4-(4-1H-Tetrazol-5-yl- phenyl)-5-(3,4,5-trimethoxy- phenyl)-isoxazole 81

4-[4-(1-Methyl-1H-tetrazol- 5-yl)-phenyl]-5-(3,4,5-trimethoxy-phenyl)-isoxazole  82

4-(1-Methyl-1H-indol-5-yl)- 5-(3,4,5-trimethoxy-phenyl)- isoxazole  83

4-(Pyridazin-4-yl)-5-(4- methoxy-benzo[1,3]dioxol- 6-yl)-isoxazole  84

4-(Pyrimidin-5-yl)-5-(4- methoxy-benzo[1,3]dioxol- 6-yl)-isoxazole  85

4-(Pyridin-3-yl)-5-(4- methoxy-benzo[1,3]dioxol- 6-yl)-isoxazole,hydrochloric acid salt  86

4-(3-Mercapto-4-methoxy- phenyl)-5-(4-methoxy- benzo[1,3]dioxol-6-yl)-isoxazole  87

4-(3-Phosphonosulfanyl-4- methoxy-phenyl)-5-(4-methoxy-benzo[1,3]dioxol- 6-yl)-isoxazole  88

4-(3-Acetylamino-4- methoxy-phenyl)-5-(4- methoxy-benzo[1,3]dioxol-6-yl)-isoxazole  89

4-(3-Amino-4-methoxy- phenyl)-5-(4-methoxy- benzo[1,3]dioxol-6-yl)-isoxazole, hydrochloric acid salt  90

4-(2-Hydroxy-4-methoxy- phenyl)-5-(4-methoxy- benzo[1,3]dioxol-6-yl)-isoxazole  91

4-(2-Methoxy-pyridin-5- yl)-5-(4-methoxy- benzo[1,3]dioxol-6-yl)-isoxazole  92

4-(5-Methoxy-pyridin-2- yl)-5-(4-methoxy-benzo[1,3]dioxol-6-yl)-isoxazole  93

4-(3-Carboxy-4-methoxy- phenyl)-5-(4-methoxy- benzo[1,3]dioxol-6-yl)-isoxazole, sodium salt  94

4-(3-Methoxycarbonyl-4- methoxy-phenyl)-5-(4- methoxy-benzo[1,3]dioxol-6-yl)-isoxazole  95

4-(3-Sulfooxy-4-methoxy- phenyl)-5-(4-methoxy- benzo[1,3]dioxol-6-yl)-isoxazole, sodium salt  96

4-(3-Amino-4-methoxy- phenyl)-5-(4-methoxy- benzo[1,3]dioxol-6-yl)-isoxazole  97

4-(3,4-Dimethoxy-5 phosphonooxy-phenyl)-5-(4- methoxy-benzo[1,3]dioxol-6-yl)-isoxazole, disodium salt  98

4-(2-Phosphonooxy-4- methoxy-phenyl)-5-(4- methoxy-benzo[1,3]dioxol-6-yl)-isoxazole, disodium salt  99

4-(4-Methylsulfanyl- phenyl)-5-(4-methoxy- benzo[1,3]dioxol-6-yl)-isoxazole 100

4-(3-Phosphonooxy-4- methylsulfanyl-phenyl)-5-(4-methoxy-benzo[1,3]dioxol- 6-yl)-isoxazole, disodium salt 101

4-(3-Amino-4- methylsulfanyl-phenyl)-5-(4- methoxy-benzo[1,3]dioxol-6-yl)-isoxazole 102

4-(2,3-Dihydro-benzofuran- 6-yl)-5-(4-methoxy- benzo[1,3]dioxol-6-yl)-isoxazole 103

4-(4-Hydroxy-phenyl)-5-(4- methoxy-benzo[1,3]dioxol- 6-yl)-isoxazole,sodium salt 104

4-(4-Phosphonooxy-phenyl)- 5-(4-methoxy- benzo[1,3]dioxol-6-yl)-isoxazole 105

4-(4-1H-Tetrazol-5-yl-phenyl)-5-(4-methoxy- benzo[1,3]dioxol-6-yl)-isoxazole 106

4-[4-(1-Methyl-1H-tetrazol- 5-yl)-phenyl]-5-(4-methoxy-benzo[1,3]dioxol-6-yl)- isoxazole 107

4-(1-Methyl-1H-indol-5-yl)- 5-(4-methoxy- benzo[1,3]dioxol-6-yl)-isoxazole 108

4-(3,4,5-Trimethoxy- phenyl)-5-(1-methyl-1H- indol-5-yl)-isoxazole 109

4-(3,4,5-Trimethoxy- phenyl)-5-(3-phosphonooxy- 4-methoxy-phenyl)-isoxazole, disodium salt 110

4-(3,4,5-Trimethoxy- phenyl)-5-(N,N- dimethylamino-phenyl)- isoxazole111

4-(3,4,5-Trimethoxy- phenyl)-5-(3-amino-4- methoxy-phenyl)-isoxazole,hydrochloric acid salt 112

4-(3,4,5-Trimethoxy-phenyl)-5-[3-(3-hydroxy-2S- amino-propionamido)-4-methoxy-phenyl]-isoxazole, hydrochloric acid salt 113

4-(4-Methoxy-phenyl)-5- (2,4,5-trimethoxy-phenyl)- isoxazole 114

4-(4-Methyl-phenyl)-5- (2,4,5-trimethoxy-phenyl)-isoxazole 115

4-(4-Ethoxy-phenyl)-5- (2,4,5-trimethoxy-phenyl)-isoxazole 116

4-(4-Ethyl-phenyl)-5- (2,4,5-trimethoxy-phenyl)- isoxazole 117

4-(4-Propoxy-phenyl)-5- (2,4,5-trimethoxy-phenyl)- isoxazole 118

4-(4-Propyl-phenyl)-5- (2,4,5-trimethoxy-phenyl)-isoxazole 119

4-(4-Butoxy-phenyl)-5- (2,4,5-trimethoxy-phenyl)- isoxazole 120

4-(4-Butyl-phenyl)-5- (2,4,5-trimethoxy-phenyl)- isoxazole 121

4-(4-Bromo-phenyl)-5- (2,4,5-trimethoxy-phenyl)-isoxazole 122

4-(4-Chloro-phenyl)-5- (2,4,5-trimethoxy-phenyl)-isoxazole 123

4-(4-Fluoro-phenyl)-5- (2,4,5-trimethoxy-phenyl)-isoxazole 124

4-(4-Nitro-phenyl)-5-(2,4,5- trimethoxy-phenyl)- isoxazole 125

4-[4-(N,N-Dimethylamino)- phenyl]-5-(2,4,5-trimethoxy- phenyl)-isoxazole126

4-(3,4-Dimethoxy-phenyl)- 5-(2,4,5-trimethoxy-phenyl)- isoxazole 127

4-(3-Hydroxy-4-methoxy- phenyl)-5-(2,4,5-trimethoxy- phenyl)-isoxazole128

4-(3,4,5-Trimethoxy- phenyl)-5-(2,4,5-trimethoxy- phenyl)-isoxazole 129

4-(4-Methoxy-phenyl)-5- (2,3,5-trimethoxy-phenyl)- isoxazole 130

4-(4-Methyl-phenyl)-5- (2,3,5-trimethoxy-phenyl)- isoxazole 131

4-(4-Ethoxy-phenyl)-5- (2,3,5-trimethoxy-phenyl)- isoxazole 132

4-(4-Ethyl-phenyl)-5- (2,3,5-trimethoxy-phenyl)- isoxazole 133

4-(4-Propoxy-phenyl)-5- (2,3,5-trimethoxy-phenyl)- isoxazole 134

4-(4-Propyl-phenyl)-5- (2,3,5-trimethoxy-phenyl)- isoxazole 135

4-(4-Butoxy-phenyl)-5- (2,3,5-trimethoxy-phenyl)- isoxazole 136

4-(4-Butyl-phenyl)-5- (2,3,5-trimethoxy-phenyl)- isoxazole 137

4-(4-Bromo-phenyl)-5- (2,3,5-trimethoxy-phenyl)- isoxazole 138

4-(4-Chloro-phenyl)-5- (2,3,5-trimethoxy-phenyl)- isoxazole 139

4-(4-Fluoro-phenyl)-5- (2,3,5-trimethoxy-phenyl)- isoxazole 140

4-(4-Nitro-phenyl)-5- (2,3,5-trimethoxy-phenyl)- isoxazole 141

4-[4-(N,N-Dimethylamino)- phenyl]-5-(2,3,5-trimethoxy- phenyl)-isoxazole142

4-(3,4-Dimethoxy-phenyl)- 5-(2,3,5-trimethoxy-phenyl)- isoxazole 143

4-(3-Hydroxy-4-methoxy- phenyl)-5-(2,3,5-trimethoxy- phenyl)-isoxazole144

4-(3,4,5-Trimethoxy- phenyl)-5-(2,3,5-trimethoxy- phenyl)-isoxazole 145

4-(2,3,4,5-Tetramethoxy- phenyl)-5-(4-methoxy- phenyl)-isoxazole 146

4-(2,3,4,5-Tetramethoxy- phenyl)-5-(4-methyl- phenyl)-isoxazole 147

4-(2,3,4,5-Tetramethoxy- phenyl)-5-(4-ethoxy- phenyl)-isoxazole 148

4-(2,3,4,5-Tetramethoxy- phenyl)-5-(4-ethyl-phenyl)- isoxazole 149

4-(2,3,4,5-Tetramethoxy- phenyl)-5-(4-propoxy- phenyl)-isoxazole 150

4-(2,3,4,5-Tetramethoxy- phenyl)-5-(4-propyl-phenyl)- isoxazole 151

4-(2,3,4,5-Tetramethoxy- phenyl)-5-(4-butoxy- phenyl)-isoxazole 152

4-(2,3,4,5-Tetramethoxy- phenyl)-5-(4-butyl-phenyl)- isoxazole 153

4-(2,3,4,5-Tetramethoxy- phenyl)-5-(4-bromo-phenyl)- isoxazole 154

4-(2,3,4,5-Tetramethoxy- phenyl)-5-(4-chloro-phenyl)- isoxazole 155

4-(2,3,4,5-Tetramethoxy- phenyl)-5-(4-fluoro-phenyl)- isoxazole 156

4-(2,3,4,5-Tetramethoxy- phenyl)-5-(4-nitro-phenyl)- isoxazole 157

4-(2,3,4,5-Tetramethoxy- phenyl)-5-[4-(N,N,- dimethylamino)-phenyl]-isoxazole 158

4-(2,3,4,5-Tetramethoxy- phenyl)-5-(3,4-dimethoxy- phenyl)-isoxazole 159

4-(2,3,4,5-Tetramethoxy- phenyl)-5-(3-hydroxy-4-methoxy-phenyl)-isoxazole 160

4-(2,3,4,5-Tetramethoxy- phenyl)-5-(3,4,5-trimethoxy- phenyl)-isoxazole161

4-(2,3-Dihydro- benzo[1,4]dioxin-6-yl)-5-(3,4-dimethoxy-phenyl)-isoxazole 162

4-(3,4-Dimethy-phenyl)-5- (2-hydroxy-4-methoxy-5-ethyl-phenyl)-isoxazole 163

4-(4-Chloro-phenyl)-5-(2- hydroxy-4-methoxy-5-ethyl- phenyl)-isoxazole164

4-(4-Methyl-phenyl)-5-(2- hydroxy-4-methoxy-5-ethyl- phenyl)-isoxazole165

4-(4-Amino-phenyl)-5-(2- hydroxy-4-methoxy-5-ethyl- phenyl)-isoxazole166

4-(4-Trifluoromethyl- phenyl)-5-(2-hydroxy-4- methoxy-5-ethyl-phenyl)-isoxazole 167

4-(4-Methoxy-phenyl)-5-(2- hydroxy-4-methoxy-5-ethyl- phenyl)-isoxazole168

4-(3,4,5-Trimethoxy- phenyl)-5-(4-bromo-phenyl)-isoxazole 169

2-amino-N-(2-methoxy-5-[5- (3,4,5-trimethoxy-phenyl)-isoxazol-4-yl)-phenyl) acetamide hydrochloride 170

2-amino-3-hydroxy-N-(2- methoxy-5-[5-(3,4,5- trimethoxy-phenyl)-isoxazol-4-yl)-phenyl) propanamide hydrochloride 171

2-amino-N-(2-methoxy-5-[5- (3,4,5-trimethoxy-phenyl)-isoxazol-4-yl)-phenyl) propanamide 172

2-amino-N-(2-methoxy-5-[5- (3,4,5-trimethoxy-phenyl)-isoxazol-4-yl)-phenyl)-4- (methylthio)butanamide hydrochloride 173

2-amino-N-(2-methoxy-5-[5- (3,4,5-trimethoxy-phenyl)-isoxazol-4-yl)-phenyl) butanamide 174

2-amino-N-(2-methoxy-5-[5- (3,4,5-trimethoxy-phenyl)-isoxazol-4-yl)-phenyl)-3- phenylpropanamide hydrochloride 175

2-amino-N-(2-methoxy-5-[5- (3,4,5-trimethoxy-phenyl)-isoxazol-4-yl)-phenyl)-4- methylpentanamide hydrochloride 176

2-amino-N-(2-methoxy-5-[5- (3,4,5-trimethoxy-phenyl)-isoxazol-4-yl)-phenyl)-3-(4- methoxyphenyl) propanamide hydrochloride177

2-methoxy-5-[5-(3,4,5- trimethoxy-phenyl)- isoxazol-4-yl)-phenyldihydrogen phosphate 178

Sodium 2-methoxy-5-[5- (3,4,5-trimethoxy-phenyl)-isoxazol-4-yl)-phenylphosphate 179

1-{2-methoxy-5-[5-(3,4,5- trimethoxy-phenyl)- isoxazol-4-yl]-phenylcarbomoyl}-2- methyl-propyl-ammonium chloride 180

1-{2-methoxy-5-[5-(3,4,5- trimethoxy-phenyl)- isoxazol-4-phenylcarbomoyl}-2- methyl-butyl-ammonium chloride 181

2-hydroxy-1-{2-methoxy-5- [5-(3,4,5-trimethoxy- phenyl)-isoxazol-4-yl]-phenylcarbomoyl}-propyl- ammonium chloride 182

2-(4-hydroxy-phenyl)-1-{2- methoxy-5-[5-(3,4,5- trimethoxy-phenyl)-isoxazol-4-yl]- phenylcarbomoyl}-ethyl- ammonium chloride 183

C-{2-methoxy-5-[5-(3,4,5- trimethoxy-phenyl)- isoxazol-4-yl]-phenylcarbomoyl}-C- phenyl-methyl-ammonium chloride 184

2-(1H-indol-2-yl)-1-{2- methoxy-5-[5-(3,4,5- trimethoxy-phenyl)-isoxazol-4-yl] phenylcarbomoyl}-ethyl- ammonium chloride 185

2-benzofuran-2-yl-1-{2- methoxy-5-[5-(3,4,5- trimethoxy-phenyl)-isoxazol-4-yl] phenylcarbomoyl}-ethyl- ammonium chloride 186

2-carboxyl-1-{2-methoxy-5- [5-(3,4,5-trimethoxy- phenyl)-isoxazol-4-yl]-phenylcarbomoyl}-ethyl- ammonium chloride 187

3-carboxyl-1-{2-methoxy-5- [5-(3,4,5-trimethoxy- phenyl)-isoxazol-4-yl]-phenylcarbomoyl}-propyl- ammonium chloride 188

3-carbamoyl-1-{2-methoxy- 5-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl]- phenylcarbomoyl}-propyl- ammonium chloride 189

2-carbamoyl-1-1{-methoxy- 5-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl]- phenylcarbomoyl}-ethyl- ammonium chloride 190

2-(3H-imidazol-4-yl)-1-{2- methoxy-5-[5-(3,4,5- trimethoxy-phenyl)-isoxazol-4-yl]- phenylcarbomoyl}-ethyl- ammonium chloride 191

5-amino-1-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)- isoxazol-4-yl]-phenylcarbomoyl}-pentyl- ammonium chloride 192

4-guanidino-1-{2-methoxy- 5-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl]- phenylcarbomoyl}-butyl- ammonium chloride 193

N-{2-methoxy-5-[5-(3,4,5- trimethoxy-phenyl)- isoxazol-4-yl]-phenyl}succinamic acid 194

4-{2-methoxy-5-[5-(3,4,5- trimethoxy-phenyl)- isoxazol-4-yl]-phenylcarbamoyl}-butyric acid 195

2-{2-methoxy-5-[5-(3,4,5- trimethoxy-phenyl)- isoxazol-4-yl]phenylcarbamoyl}-ethyl- ammonium chloride 196

3-(2-methoxy-ethoxy)-N-{2- methoxy-5-[5-(3,4,5- trimethoxy-phenyl)-isoxazol-4-yl]-phenyl}- propionamide 197

3-(2-PEG)-N-{2-methoxy-5- [5-(3,4,5-trimethoxy- phenyl)-isoxazol-4-yl]-phenyl}-propionamide 198

N-{2-methoxy-5-[5-(3,4,5- trimethoxy-phenyl)-isoxazol-4-yl]-phenyl}-3-(2- methylamino-ethylamino)- propionamide 199

3-PEG-N-{2-methoxy-5-[5- (3,4,5-trimethoxy-phenyl)- isoxazol-4-yl]-phenylcarbamoyl}-methyl)- propionamide 200

N-{2-methoxy-5-[5-(3,4,5- trimethoxy-phenyl)- isoxazol-4-yl]-phenylcarbamoyl}-methyl)- succinamic acid 201

{2-methoxy-5-[5-(3,4,5- trimethoxy-phenyl)- isoxazol-4-yl]-phenyl}-carbamic acid 2-methoxy- ethyl ester 202

2-methoxy-5-(5-(3,4,5- trimethoxyphenyl)isoxazol-4-yl)phenylcarbamate-PEG 203

3-amino-N-[4-guanadino-1- {2-methoxy-5-[5-(3,4,5- trimethoxy-phenyl)-isoxazol-4-yl]- phenylcarbamoyl}- butylcarbamoyl)-methyl]- succinamicacid 204

2-amino-N-(2-methoxy-5-[5- (3,4,5-trimethoxy-phenyl)-isoxazol-4-yl)-phenyl) propanamide hydrochloride 205

2-amino-N-(2-methoxy-5-[3- (3,4,5-trimethoxy-phenyl)-isoxazol-4-yl)-phenyl) acetamide hydrochloride 206

2-amino-3-hydroxy-N-(2- methoxy-5-[3-(3,4,5- trimethoxy-phenyl)-isoxazol-4-yl)-phenyl) propanamide hydrochloride 207

2-amino-N-(2-methoxy-5-[3- (3,4,5-trimethoxy-phenyl)-isoxazol-4-yl)-phenyl) propanamide 208

2-amino-N-(2-methoxy-5-[3- (3,4,5-trimethoxy-phenyl)-isoxazol-4-yl)-phenyl)-4- (methylthio)butanamide hydrochloride 209

2-amino-N-(2-methoxy-5-[3- (3,4,5-trimethoxy-phenyl)-isoxazol-4-yl)-phenyl) butanamide 210

2-amino-N-(2-methoxy-5-[3- (3,4,5-trimethoxy-phenyl)-isoxazol-4-yl)-phenyl)-3- phenylpropanamide hydrochloride 211

2-amino-N-(2-methoxy-5-[3- (3,4,5-trimethoxy-phenyl)-isoxazol-4-yl)-phenyl)-4- methylpentanamide hydrochloride 212

2-amino-N-(2-methoxy-5-[3- (3,4,5-trimethoxy-phenyl)-isoxazol-4-yl)-phenyl)-3-(4- methoxyphenyl) propanamide hydrochloride213

2-methoxy-5-[3-(3,4,5- trimethoxy-phenyl)- isoxazol-4-yl)-phenyldihydrogen phosphate 214

Sodium 2-methoxy-5-[3- (3,4,5-trimethoxy-phenyl)-isoxazol-4-yl)-phenylphosphate 215

1-{2-methoxy-3-[5-(3,4,5- trimethoxy-phenyl)- isoxazol-4-yl]-phenylcarbomoyl}-2- methyl-propyl-ammonium chloride 216

1-{2-methoxy-5-[3-(3,4,5- trimethoxy-phenyl)- isoxazol-4-yl]-phenylcarbomoyl}-2- methyl-butyl-ammonium chloride 217

2-hydroxy-1-{2-methoxy-5- [3-(3,4,5-trimethoxy- phenyl)-isoxazol-4-yl]-phenylcarbomoyl}-propyl- ammonium chloride 218

2-(4-hydroxy-phenyl)-1-{2- methoxy-5-[3-(3,4,5- trimethoxy-phenyl)-isoxazol-4-yl] phenylcarbomoyl}-ethyl- ammonium chloride 219

C-{2-methoxy-5-[3-(3,4,5- trimethoxy-phenyl)- isoxazol-4-yl]-phenylcarbomoyl}-C- phenyl-methyl-ammonium chloride 220

2-(1H-indol-2-yl)-1-{2- methoxy-5-[3-(3,4,5- trimethoxy-phenyl)-isoxazol-4-yl]- phenylcarbomoyl}-ethyl- ammonium chloride 221

2-benzofuran-2-yl-1-{2- methoxy-5-[3-(3,4,5- trimethoxy-phenyl)-isoxazol-4-yl]- phenylcarbomoyl}-ethyl- ammonium chloride 222

2-carboxyl-1-{2-methoxy-5- [3-(3,4,5-trimethoxy- phenyl)-isoxazol-4-yl]-phenylcarbomoyl}-ethyl- ammonium chloride 223

3-carboxyl-1-{2-methoxy-5- [3-(3,4,5-trimethoxy- phenyl)-isoxazol-4-yl]-phenylcarbomoyl}-propyl- ammonium chloride 224

3-carbamoyl-1-{2-methoxy- 5-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl]- phenylcarbomoyl}-propyl- ammonium chloride 225

2-carbamoyl-1-{2-methoxy- 5-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl]- phenylcarbomoyl}-ethyl- ammonium chloride 226

2-(3H-imidazol-4-yl)-1-{2- methoxy-5-[3-(3,4,5- trimethoxy-phenyl)-isoxazol-4-yl]- phenylcarbomoyl}-ethyl- ammonium chloride 227

5-amino-1-{2-methoxy-5-[3- (3,4,5-trimethoxy-phenyl)- isoxazol-4-yl]-phenylcarbomoyl}-pentyl- ammonium chloride 228

4-guanidino-1-{2-methoxy- 5-[3-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl]- phenylcarbomoyl}-butyl- ammonium chloride 229

N-{2-methoxy-5-[3-(3,4,5- trimethoxy-phenyl)- isoxazol-4-yl]-phenyl}succinamic acid 230

4-{2-methoxy-5-[3-(3,4,5- trimethoxy-phenyl)- isoxazol-4-yl]-phenylcarbamoyl}-butyric acid 231

2-{2-methoxy-5-[3-(3,4,5- trimethoxy-phenyl)- isoxazol-4-yl]-phenylcarbamoyl}-ethyl- ammonium chloride 232

3-(2-methoxy-ethoxy)-N-{2- methoxy-5-[3-(3,4,5- trimethoxy-phenyl)-isoxazol-4-yl]-phenyl}- propionamide 233

3-(2-PEG)-N-{2-methoxy-5- [3-(3,4,5-trimethoxy- phenyl)-isoxazol-4-yl]-phenyl}-propionamide 234

N-{2-methoxy-5-[3-(3,4,5- trimethoxy-phenyl)-isoxazol-4-yl]-phenyl}-3-(2- methylamino-ethylamino)- propionamide 235

3-PEG-N-{2-methoxy-5-[3- (3,4,5-trimethoxy-phenyl)- isoxazol-4-yl]-phenylcarbanoyl}-methyl)- propionamide 236

N-{2-methoxy-5-[3-(3,4,5- trimethoxy-phenyl)- isoxazol-4-yl]-phenylcarbamoyl}-methyl)- succinamic acid 237

{2-methoxy-5-[3-(3,4,5- trimethoxy-phenyl)- isoxazol-4-yl]-phenyl}-carbamic acid 2-methoxy- ethyl ester 238

2-methoxy-5-(3-(3,4,5- trimethoxypheny)isoxazol-4-yl)phenylcarbamate-PEG 239

3-amino-N-[4-guanadino-1- {2-methoxy-5-[3-(3,4,5- trimethoxy-phenyl)-isoxazol-4-yl]- butylcarbamoyl}- butylcarbamoyl)-methyl]- succinamicacid 240

2-amino-N-(2-methoxy-5-[3- (3,4,5-trimethoxy-phenyl)-isoxazol-4-yl)-phenyl) propanamide hydrochloride 241

methyl2-(2-(2-methoxy-5- (5-(3,4,5-trimethoxyphenyl)isoxazol-4-yl)phenylamino)- 2-oxoethylamino)acetate 242

4-amino-5-(2-methoxy-5-(5- (3,4,5-trimethoxyphenyl)isoxazol-4-yl)phenylamino)- 5-oxopentanoic acid hydrochloride 243

3-amino-N-(2-methoxy-5-(5- (3,4,5-trimethoxyphenyl)isoxazol-4-yl)phenyl) propanamide hydrochloride 244

3-amino-N-(2-methoxy-5-(5- (3,4,5-trimethoxyphenyl)isoxazol-4-yl)phenyl)-4- methylpentanamide hydrochloride 245

methyl2-(2-(2-methoxy-5- (3-(3,4,5-trimethoxyphenyl)isoxazol-4-yl)phenylamino)- 2-oxoethylamino)acetate 246

4-amino-5-(2-methoxy-5-(3- (3,4,5-trimethoxyphenyl)isoxazol-4-yl)phenylamino)- 5-oxopentanoic acid hydrochloride 247

3-amino-N-(2-methoxy-5-(3- (3,4,5-trimethoxyphenyl)isoxazol-4-yl)phenyl) propanamide hydrochloride 248

3-amino-N-(2-methoxy-5-(3- (3,4,5-trimethoxyphenyl)isoxazol-4-yhphenyl)-4- methylpentanamide hydrochloride 249

2-methoxy-5-(5-(3,4,5- trimethoxyphenyl)isoxazol- 4-yl)aniline 250

2-methoxy-5-(3-(3,4,5- trimethoxyphenyl)isoxazol- 4-yl)aniline  1b

4-(4-Bromo-phenyl)-3- (3,4,5-trimethoxy-phenyl)- isoxazole  2b

4-(Naphthalen-2-yl)-3-(2- hydroxy-4-methoxy-5-ethyl- phenyl)-isoxazole 3b

4-(4-Methoxy-phenyl)-3- (3,4,5-trimethoxy-phenyl)- isoxazole  4b

4-(4-Iodo-phenyl)-3-(2- hydroxy-4-methoxy-5- ethyl-phenyl)-isoxazole  5b

4-Phenyl-3-(2-hydroxy-4- methoxy-5-propyl-phenyl)- isoxazole  6b

4-(4-Bromo-phenyl)-3-(2- hydroxy-4-methoxy-5-ethyl- phenyl)-isoxazole 7b

4-(2,3-Dihydro- benzo[1,4]di-oxin-6-yl)-3- (2-hydroxy-4-methoxy-5-propyl-phenyl)-isoxazole  8b

4-(4-hydroxy-phenyl)-3- (3,4,5-trihydroxy-phenyl)- isoxazole  9b

4-(4-Iodo-phenyl)-3- (3,4,5-trimethoxy-phenyl)- isoxazole  10b

4-(3-Fluoro-4-methoxy- phenyl)-3-(3,4,5-trimethoxy- phenyl)-isoxazole 11b

4-(4-Nitro-phenyl)-3- (3,4,5-trimethoxy-phenyl)- isoxazole  12b

4-(4-Amino-phenyl)-3- (3,4,5-trimethoxy-phenyl)- isoxazole  13b

4-(4′-Methoxy-biphenyl-4- yl)-3-(3,4,5-trimethoxy- phenyl)-isoxazole 14b

4-[4-(pyridine-3-yl)-phenyl]- 3-(3,4,5-trimethoxy-phenyl)- isoxazole 15b

4-[4-(pyridine-4-yl)-phenyl]- 3-(3,4,5-trimethoxy-phenyl)- isoxazole 16b

4-[4-(pyridine-2-yl)-phenyl]- 3-(3,4,5-trimethoxy-phenyl)- isoxazole 17b

4-(Quinolin-7-yl)-3- (3,4,5-trimethoxy-phenyl)- isoxazole  18b

4-(Pyridin-4-yl)-3- (3,4,5-trimethoxy-phenyl)- isoxazole  19b

4-(Isoquinolin-7-yl)-3- (3,4,5-trimethoxy-phenyl)- isoxazole  20b

4-(1-Methyl-1H-indol-5-yl)- 3-(3,4,5-trimethoxy-phenyl)- isoxazole  21b

4-(4-Methoxy-phenyl)-3- (benzo[1,3]dioxol-5-yl)- isoxazole  22b

4-(4-Methoxy-phenyl)-3- (1-ethyl-1H-indol-6-yl)- isoxazole  23b

4-(4-Carboxy-phenyl)-3- (3,4,5-trimethoxy-phenyl)- isoxazole  24b

4-(4-Methoxycarbonyl- phenyl)-3-(3,4,5-trimethoxy- phenyl)-isoxazole 25b

4-[4-(Oxazol-2-yl)-phenyl]- 3-(3,4,5-trimethoxy-phenyl)- isoxazole  26b

4-(4-Methoxy-phenyl)-3- (3,4,5-triethyl-phenyl)- isoxazole  27b

4-(4-Iodo-phenyl)-3- (3,4,5-triethyl-phenyl)- isoxazole  28b

4-(3-Fluoro-4-methoxy- phenyl)-3-(3,4,5-triethyl- phenyl)-isoxazole  29b

4-(4-Nitro-phenyl)-3- (3,4,5-triethyl-phenyl)- isoxazole  30b

4-(4-N,N-dimethylamino- phenyl)-3-(3,4,5-triethyl- phenyl)-isoxazole 31b

4-(4-Methoxy-phenyl)-3- (3,4,5-trimethyl-phenyl)- isoxazole  32b

4-[4-(Pyridin-3-yl)-phenyl]- 3-(3,4,5-triethyl-phenyl)- isoxazole  33b

4-[4-(Pyridin-4-yl)-phenyl]- 3-(3,4,5-triethyl-phenyl)- isoxazole  34b

4-[4-(Pyridin-2-yl)-phenyl]- 3-(3,4,5-triethyl-phenyl)- isoxazole  35b

4-(Quinolin-7-yl)-3- (3,4,5-triethyl-phenyl)- isoxazole  36b

4-(Pyridin-4-yl)-3-(3,4,5- triethyl-phenyl)-isoxazole  37b

4-(Isoquinolin-7-yl)-3- (3,4,5-triethyl-phenyl)- isoxazole  38b

4-(1H-Indol-5-yl)-3- (3,4,5-triethyl-phenyl)- isoxazole  39b

4-(4-Methoxy-phenyl)-3- (benzo[1,3]dioxol-5-yl)- isoxazole  40b

4-(4-Methoxy-phenyl)-3- [1-isopropyl-1H-indol-6-yl)- isoxazole  41b

4-(4-Methoxy-phenyl)-3- (2,3,4-trimethoxy-phenyl)- isoxazole  42b

4-(3-Hydroxy-4-methoxy- phenyl)-3-(3,4,5-trimethoxy- phenyl)-isoxazole 43b

4-[3-(Ethyl-hydroxy- phosphoryloxy)-4-methoxy-phenyl]-3-(3,4,5-trimethoxy- phenyl)-isoxazole  44b

4-(4-Methoxy-phenyl)-3-(2- hydroxy-4-methoxy-5-ethyl- phenyl)-isoxazole; 45b

4-(4-Isopropyl-phenyl)-3- (3,4,5-trimethoxy-phenyl)- isoxazole  46b

4-(2,3-Dihydro- benzo[1,4]dioxin-6-yl)-3- (3,4,5-trimethoxy-phenyl)-isoxazole  47b

4-(4-Ethyl-phenyl)-3- (3,4,5-trimethoxy-phenyl)- isoxazole  48b

4-(5-Methoxy-pyridin-2-yl)- 3-(3,4,5-trimethoxy-phenyl)- isoxazole  49b

4-(4-Methoxy-phenyl)-3- (2,3,4-trimethoxy-pyridin- 6-yl)-isoxazole  50b

4-(4-Methoxy-phenyl)-3- (3,5-dimethoxy-4- methoxycarbonyl-phenyl)-isoxazole  51b

4-(4-Methoxy-phenyl)-3- (3,5-diacetoxy-phenyl)- isoxazole  52b

4-(2-Methoxy-pyridin-5-yl)- 3-(3,4,5-trimethoxy-phenyl)- isoxazole  53b

4-(4-Methoxy-phenyl)-3- (1-methyl-5-methoxy- 1H-indol-7-yl)-isoxazole 54b

4-(4-Methoxy-phenyl)-3- (1-ethyl-1H-indol-7-yl)- isoxazole  55b

4-(4-Methoxy-phenyl)-3- (benzo[1,3]dioxol-4-yl)- isoxazole  56b

4-(2-Hydroxy-4-methoxy- phenyl)-3-(3,4,5- trimethoxy)-isoxazole  57b

4-[2-(Ethyl-hydroxy- phosphoryloxy)-4-methoxy-phenyl]-3-(3,4,5-trimethoxy- phenyl)-isoxazole  58b

4-(Pyridazin-4-yl)-3-(3,4,5- trimethoxy-phenyl)- isoxazole  59b

4-(Pyrimidin-5-yl)-3-(3,4,5- trimethoxy-phenyl)- isoxazole  60b

4-(Pyridin-3-yl)-3-(3,4,5- trimethoxy-phenyl)- isoxazole, hydrochloricacid salt  61b

4-(3-Mercapto-4-methoxy- phenyl)-3-(3,4,5-trimethoxy- phenyl)-isoxazole 62b

4-(3-Phosphonosulfanyl-4- methoxy-phenyl)-3-(3,4,5- trimethoxy-phenyl)-isoxazole, disodium salt  63b

4-(3-Acetylamine-4- methoxy-phenyl)-3-(3,4,5- trimethoxy-phenyl)-isoxazole  64b

4-(3-Amino-4-methoxy- phenyl)-3-(3,4,5-trimethoxy- phenyl)-isoxazole,hydrochloric acid salt  65b

4-(2-Hydroxy-4-methoxy- phenyl)-3-(3,4,5-trimethoxy- phenyl)-isoxazole 66b

4-(2-Methoxy-pyridine-5- yl)-3-(3,4,5-trimethoxy- phenyl)-isoxazole  67b

4-(5-Methoxy-pyridine-2- yl)-3-(3,4,5-trimethoxy- phenyl)-isoxazole  68b

4-(3-Carboxy-4-methoxy- phenyl)-3-(3,4,5-trimethoxy- phenyl)-isoxazole,sodium salt  69b

4-(3-Methoxycarbonyl-4- methoxy-phenyl)-3-(3,4,5-trimethoxy-phenyl)-isoxazole  70b

4-(3-Sulfooxy-4-methoxy- phenyl)-3-(3,4,5-trimethoxy- phenyl)-isoxazole,sodium salt  71b

4-(2-Amino-4-methoxy- phenyl)-3-(3,4,5-trimethoxy- phenyl)-isoxazole 72b

4-(3,4-Dimethoxy-5- phosphonooxy-phenyl)-3- (3,4,5-trimethoxy-phenyl)-isoxazole, disodium salt  73b

4-(2-Phosphonooxy-4- methoxy-phenyl)-3-(3,4,5- trimethoxy-phenyl)-isoxazole, disodium salt  74b

4-(4-Methylsulfanyl- phenyl)-3-(3,4,5-trimethoxy- phenyl)-isoxazole  75b

4-(3-Phosphonooxy-4- methylsulfanyl-phenyl)-3-(3,4,5-trimethoxy-phenyl)- isoxazole, disodium salt  76b

4-(3-Amino-4- methylsulfanyl-phenyl)-3- (3,4,5-trimethoxy-phenyl)-isoxazole  77b

4-(2,3-Dihydro-benzofuran- 6-yl)-3-(3,4,5-trimethoxy- phenyl)-isoxazole 78b

4-(4-Hydroxy-phenyl)-3- (3,4,5-trimethoxy-phenyl)- isoxazole, sodiumsalt  79b

4-(4-Phosphonooxy-phenyl)- 3-(3,4,5-trimethoxy-phenyl)- isoxazole,disodium salt  80b

4-(4-1H-Tetrazol-5-yl- phenyl)-3-(3,4,5-trimethoxy- phenyl)-isoxazole 81b

4-[4-(1-Methyl-1H-tetrazol- 5-yl)-phenyl]-3-(3,4,5- trimethoxy-phenyl)-isoxazole  82b

4-(1-Methyl-1H-indol-5-yl)- 3-(3,4,5-trimethoxy-phenyl)- isoxazole  83b

4-(Pyridazin-4-yl)-3-(4- methoxy-benzo[1,3]dioxol- 6-yl)-isoxazole  84b

4-(Pyrimidin-5-yl)-3-(4- methoxy-benzo[1,3]dioxol- 6-yl)-isoxazole  85b

4-(Pyridin-3-yl)-3-(4- methoxy-benzo[1,3]dioxol- 6-yl)-isoxazole,hydrochloric acid salt  86b

4-(3-Mercapto-4-methoxy- phenyl)-3-(4-methoxy- benzo[1,3]dioxol-6-yl)-isoxazole  87b

4-(3-Phosphonosulfanyl-4- methoxy-phenyl)-3-(4-methoxy-benzo[1,3]dioxol- 6-yl)-isoxazole  88b

4-(3-Acetylamine-4- methoxy-phenyl)-3-(4- methoxy-benzo[1,3]dioxol-6-yl)-isoxazole  89b

4-(3-Amino-4-methoxy- phenyl)-3-(4-methoxy- benzo[1,3]dioxol-6-yl)-isoxazole, hydrochloric acid salt  90b

4-(2-Hydroxy-4-methoxy- phenyl)-3-(4-methoxy- benzo[1,3]dioxol-6-yl)-isoxazole  91b

4-(2-Methoxy-pyridin-5-yl)- 3-(4-methoxy- benzo[1,3]dioxol-6-yl)-isoxazole  92b

4-(5-Methoxy-pyridin-2-yl)- 3-(4-methoxy- benzo[1,3]dioxol-6-yl)-isoxazole  93b

4-(3-Carboxy-4-methoxy- phenyl)-3-(4-methoxy- benzo[1,3]dioxol-6-yl)-isoxazole, sodium salt  94b

4-(3-Methoxycarbonyl-4- methoxy-phenyl)-3-(4- methoxy-benzo[1,3]dioxol-6-yl)-isoxazole  95b

4-(3-Sulfooxy-4-methoxy- phenyl)-3-(4-methoxy- benzo[1,3]dioxol-6-yl)-isoxazole, sodium salt  96b

4-(3-Amino-4-methoxy- phenyl)-3-(4-methoxy- benzo[1,3]dioxol-6-yl)-isoxazole  97b

4-(3,4-Dimethoxy-5 phosphonooxy-phenyl)-3-(4- methoxy-benzo[1,3]dioxol-6-yl)-isoxazole, disodium salt  98b

4-(2-Phosphonooxy-4- methoxy-phenyl)-3-(4- methoxy-benzo[1,3]dioxol-6-yl)-isoxazole, disodium salt  99b

4-(4-Methylsulfanyl- phenyl)-3-(4-methoxy- benzo[1,3]dioxol-6-yl)-isoxazole 100b

4-(3-Phosphonooxy-4- methylsulfanyl-phenyl)-3-(4-methoxy-benzo[1,3]dioxol- 6-yl)-isoxazole, disodium salt 101b

4-(3-Amino-4- methylsulfanyl-phenyl)- 3-(4-methoxy-benzo[1,3]dioxol-6-yl)- isoxazole 102b

4-(2,3-Dihydro-benzofuran- 6-yl)-3-(4-methoxy- benzo[1,3]dioxol-6-yl)-isoxazole 103b

4-(4-Hydroxy-phenyl)-3-(4- methoxy-benzo[1,3]dioxol- 6-yl)-isoxazole,sodium salt 104b

4-(4-Phosphonooxy-phenyl)- 3-(4-methoxy- benzo[1,3]dioxol-6-yl)-isoxazole 105b

4-(4-1H-Tetrazol-5-yl- phenyl)-3-(4-methoxy- benzo[1,3]dioxol-6-yl)-isoxazole 106b

4-[4-(1-Methyl-1H-tetrazol- 5-yl)-phenyl]-3-(4-methoxy-benzo[1,3]dioxol-6-yl)- isoxazole 107b

4-(1-Methyl-1H-indol-5-yl)- 3-(4-methoxy- benzo[1,3]dioxol-6-yl)-isoxazole 108b

4-(3,4,5-Trimethoxy- phenyl)-3-(1-methyl-1H- indol-5-yl)-isoxazole 109b

4-(3,4,5-Trimethoxy- phenyl)-3-(3-phosphonooxy- 4-methoxy-phenyl)-isoxazole, disodium salt 110b

4-(3,4,5-Trimethoxy- phenyl)-3-(N,N- dimethylamino-phenyl)- isoxazole111b

4-(3,4,5-Trimethoxy- phenyl)-3-(3-amino-4- methoxy-phenyl)-isoxazole,hydrochloric acid salt 112b

4-(3,4,5-Trimethoxy- phenyl)-3-[3-(3-hydroxy- 2S-amino-propionamido)-4-methoxy-phenyl]- isoxazole, hydrochloric acid salt 113b

4-(4-Methoxy-phenyl)-3- (2,4,5-trimethoxy-phenyl)- isoxazole 114b

4-(4-Methyl-phenyl)-3- (2,4,5-trimethoxy-phenyl)-isoxazole 115b

4-(4-Ethoxy-phenyl)-3- (2,4,5-trimethoxy-phenyl)-isoxazole 116b

4-(4-Ethyl-phenyl)-3- (2,4,5-trimethoxy-phenyl)-isoxazole 117b

4-(4-Propoxy-phenyl)-3- (2,4,5-trimethoxy-phenyl)- isoxazole 118b

4-(4-Propyl-phenyl)-3- (2,4,5-trimethoxy-phenyl)-isoxazole 119b

4-(4-Butoxy-phenyl)-3- (2,4,5-trimethoxy-phenyl)- isoxazole 120b

4-(4-Butyl-phenyl)-3- (2,4,5-trimethoxy-phenyl)-isoxazole 121b

4-(4-Bromo-phenyl)-3- (2,4,5-trimethoxy-phenyl)-isoxazole 122b

4-(4-Chloro-phenyl)-3- (2,4,5-trimethoxy-phenyl)-isoxazole 123b

4-(4-Fluoro-phenyl)-3- (2,4,5-trimethoxy-phenyl)-isoxazole 124b

4-(4-Nitro-phenyl)-3- (2,4,5-trimethoxy-phenyl)-isoxazole 125b

4-[4-(N,N-Dimethylamino)- phenyl]-3-(2,4,5-trimethoxy- phenyl)-isoxazole126b

4-(3,4-Dimethoxy-phenyl)- 3-(2,4,5-trimethoxy-phenyl)- isoxazole 127b

4-(3-Hydroxy-4-methoxy- phenyl)-3-(2,4,5-trimethoxy- phenyl)-isoxazole128b

4-(3,4,5-Trimethoxy- phenyl)-3-(2,4,5-trimethoxy- phenyl)-isoxazole 129b

4-(4-Methoxy-phenyl)-3- (2,3,5-trimethoxy-phenyl)- isoxazole 130b

4-(4-Methyl-phenyl)-3- (2,3,5-trimethoxy-phenyl)- isoxazole 131b

4-(4-Ethoxy-phenyl)-3- (2,3,5-trimethoxy-phenyl)- isoxazole 132b

4-(4-Ethyl-phenyl)-3- (2,3,5-trimethoxy-phenyl)- isoxazole 133b

4-(4-Propoxy-phenyl)-3- (2,3,5-trimethoxy-phenyl)- isoxazole 134b

4-(4-Propyl-phenyl)-3- (2,3,5-trimethoxy-phenyl)- isoxazole 135b

4-(4-Butoxy-phenyl)-3- (2,3,5-trimethoxy-phenyl)- isoxazole 136b

4-(4-Butyl-phenyl)-3- (2,3,5-trimethoxy-phenyl)- isoxazole 137b

4-(4-Bromo-phenyl)-3- (2,3,5-trimethoxy-phenyl)- isoxazole 138b

4-(4-Chloro-phenyl)-3- (2,3,5-trimethoxy-phenyl)- isoxazole 139b

4-(4-Fluoro-phenyl)-3- (2,3,5-trimethoxy-phenyl)- isoxazole 140b

4-(4-Nitro-phenyl)-3- (2,3,5-trimethoxy-phenyl)- isoxazole 141b

4-[4-(N,N-Dimethylamino)- phenyl]-3-(2,3,5-trimethoxy- phenyl)-isoxazole142b

4-(3,4-Dimethoxy-phenyl)- 3-(2,3,5-trimethoxy-phenyl)- isoxazole 143b

4-(3-Hydroxy-4-methoxy- phenyl)-3-(2,3,5-trimethoxy- phenyl)-isoxazole144b

4-(3,4,5-Trimethoxy- phenyl)-3-(2,3,5-trimethoxy- phenyl)-isoxazole 145b

4-(2,3,4,5-Tetramethoxy- phenyl)-3-(4-methoxy- phenyl)-isoxazole 146b

4-(2,3,4,5-Tetramethoxy- phenyl)-3-(4-methyl- phenyl)-isoxazole 147b

4-(2,3,4,5-Tetramethoxy- phenyl)-3-(4-ethoxy- phenyl)-isoxazole 148b

4-(2,3,4,5-Tetramethoxy- phenyl)-3-(4-ethyl-phenyl)- isoxazole 149b

4-(2,3,4,5-Tetramethoxy- phenyl)-3-(4-propoxy- phenyl)-isoxazole 150b

4-(2,3,4,5-Tetramethoxy- phenyl)-3-(4-propyl-phenyl)- isoxazole 151b

4-(2,3,4,5-Tetramethoxy- phenyl)-3-(4-butoxy- phenyl)-isoxazole 152b

4-(2,3,4,5-Tetramethoxy- phenyl)-3-(4-butyl-phenyl)- isoxazole 153b

4-(2,3,4,5-Tetramethoxy- phenyl)-3-(4-bromo-phenyl)- isoxazole 154b

4-(2,3,4,5-Tetramethoxy- phenyl)-3-(4-chloro-phenyl)- isoxazole 155b

4-(2,3,4,5-Tetramethoxy- phenyl)-3-(4-fluoro-phenyl)- isoxazole 156b

4-(2,3,4,5-Tetramethoxy- phenyl)-3-(4-nitro-phenyl)- isoxazole 157b

4-(2,3,4,5-Tetramethoxy- phenyl)-3-[4-(N,N,- dimethylamino)-phenyl]-isoxazole 158b

4-(2,3,4,5-Tetramethoxy- phenyl)-3-(3,4-dimethoxy- phenyl)-isoxazole159b

4-(2,3,4,5-Tetramethoxy- phenyl)-3-(3-hydroxy-4-methoxy-phenyl)-isoxazole 160b

4-(2,3,4,5-Tetramethoxy- phenyl)-3-(3,4,5-trimethoxy- phenyl)-isoxazole161b

4-(2,3-Dihydro- benzo[1,4]dioxin-6-yl)-3- (3,4-dimethoxy-phenyl)-isoxazole 162b

4-(3,4-Dimethy-phenyl)-3- (2-hydroxy-4-methoxy-5-ethyl-phenyl)-isoxazole 163b

4-(4-Chloro-phenyl)-3-(2- hydroxy-4-methoxy-5- ethyl-phenyl)-isoxazole164b

4-(4-Methyl-phenyl)-3-(2- hydroxy-4-methoxy-5- ethyl-phenyl)-isoxazole165b

4-(4-Amino-phenyl)-3-(2- hydroxy-4-methoxy-5- ethyl-phenyl)-isoxazole166b

4-(4-Trifluoromethyl- phenyl)-3-(2-hydroxy-4- methoxy-5-ethyl-phenyl)-isoxazole 167b

4-(4-Methoxy-phenyl)-3-(2- hydroxy-4-methoxy-5-ethyl- phenyl)-isoxazole168b

4-(3,4,5-Trimethoxy- phenyl)-3-(4-bromo-phenyl)- isoxazole

Methods of Making the Compounds of the Invention

The compounds of the invention can be made by the methods describedherein in Example 1. In addition, the compounds of the invention can beprepared using the methods described in Olivera, et al., J. Org. Chem.(2000), 65:6398-6411; Olivera, et al., Tetrahedron (2002), 58:3021-3037;Dominguez, et al., J. Org. Chem. (1996), 61:5435-5439; Olivera, et al.,Tet. Let. (1999), 40:3479-3480; Khilya, et al. Ukrainskii KhimicheskiiZhumal (Russian Edition) (1990), 56(3); 280-286. The entire teachings ofthese references are incorporated herein by reference.

Methods of Treatment and Prevention

In one embodiment, the invention provides a method of inhibiting tubulinpolymerization in a cell, comprising contacting the cell with aneffective amount of a compound of any one of formulas (I) through (X),(IA) through (XA), (IB) through (XB), or of Table 1, or apharmaceutically acceptable salt, solvate, clathrate, and prodrugthereof, or a pharmaceutical composition comprising a compound of anyone of formulas (I) through (X), (IA) through (XA), (IB) through (XB),or of Table 1, or a pharmaceutically acceptable salt, solvate,clathrate, and prodrug thereof. Inhibition of tubulin polymerization canbe determined by determining the IC₅₀ for tubulin polymerizationinhibition for a compound as described above, or by using the methodsdescribed in Examples 7 and 8, herein.

In another embodiment, the invention provides a method of treating aproliferative disorder, such as cancer, in a subject in need thereof,comprising administering to the subject an effective amount of acompound of any one of formulas (I) through (X), (IA) through (XA), (IB)through (XB), or of Table 1, or a pharmaceutically acceptable salt,solvate, clathrate, and prodrug thereof, or a pharmaceutical compositioncomprising a compound of any one of formulas (I) through (X), (IA)through (XA), (IB) through (XB), or of Table 1, or a pharmaceuticallyacceptable salt, solvate, clathrate, and prodrug thereof. Such patientsmay be treatment naïve or may experience partial or no response toconventional therapies.

In another embodiment, the invention provides a method of blocking,occluding, or otherwise disrupting blood flow in neovasculature, in asubject in need thereof, comprising administering to the subject aneffective amount of a compound of any one of formulas (I) through (X),(IA) through (XA), (IB) through (XB), or of Table 1, or apharmaceutically acceptable salt, solvate, clathrate, and prodrugthereof, or a pharmaceutical composition comprising a compound of anyone of formulas (I) through (X), (IA) through (XA), (IB) through (XB),or of Table 1, or a pharmaceutically acceptable salt, solvate,clathrate, and prodrug thereof.

Responsiveness to treatment with the compounds of the invention in thecase of proliferative disorders can be measured by reduction in theextent or severity of the symptoms associated with the disease ordisorder and/or an increase in the longevity and/or quality of life ofthe subject compared with the absence of the treatment. Responsivenessto treatment with the compounds of the invention in the case of cancer,can be measured by a reduction in tumor mass, a reduction in the rate oftumor growth, a reduction in metastasis, a reduction in the severity ofthe symptoms associated with the cancer and/or an increase in thelongevity of the subject compared with the absence of the treatment.

Combination Therapies

The invention also provides methods of preventing, treating, managing,or ameliorating a proliferative disorder, such as cancer, or one or moresymptoms thereof, said methods comprising administering to a subject inneed thereof one or more compounds of the invention and one or moreother therapies (e.g., one or more prophylactic or therapeutic agentsthat are currently being used, have been used, are known to be useful orin development for use in the prevention, treatment or amelioration of aproliferative disorder, such as cancer, or one or more symptomsassociated with said proliferative disorder).

The prophylactic or therapeutic agents of the combination therapies ofthe invention can be administered sequentially or concurrently. In aspecific embodiment, the combination therapies of the invention compriseone or more compounds and at least one other therapy (e.g., anotherprophylactic or therapeutic agent) which has the same mechanism ofaction as said compounds (e.g., a therapeutic agent that inhibitstubulin polymerization). In another specific embodiment, the combinationtherapies of the invention comprise one or more compounds of theinvention and at least one other therapy (e.g., another prophylactic ortherapeutic agent) which has a different mechanism of action than saidcompounds. In certain embodiments, the combination therapies of thepresent invention improve the prophylactic or therapeutic effect of oneor more compounds of the invention by functioning together with thecompounds to have an additive or synergistic effect. In certainembodiments, the combination therapies of the present invention reducethe side effects associated with the therapies (e.g., prophylactic ortherapeutic agents). In certain embodiments, the combination therapiesof the present invention reduce the effective dosage of one or more ofthe therapies.

The prophylactic or therapeutic agents of the combination therapies canbe administered to a subject, preferably a human subject, in the samepharmaceutical composition. In alternative embodiments, the prophylacticor therapeutic agents of the combination therapies can be administeredconcurrently to a subject in separate pharmaceutical compositions. Theprophylactic or therapeutic agents may be administered to a subject bythe same or different routes of administration.

In a specific embodiment, a pharmaceutical composition comprising one ormore compounds of the invention is administered to a subject, preferablya human, to prevent, treat, manage, or ameliorate a proliferativedisorder, such as cancer, or one or more symptoms thereof. In accordancewith the invention, pharmaceutical compositions of the invention mayalso comprise one or more other agents (e.g., prophylactic ortherapeutic agents which are currently being used, have been used, orare known to be useful in the prevention, treatment or amelioration of aproliferative disorder or a symptom thereof).

The invention provides methods for preventing, managing, treating orameliorating a proliferative disorder, such as cancer, or one or moresymptoms thereof in a subject refractory (either completely orpartially) to existing agent therapies for such a proliferativedisorder, said methods comprising administering to said subject a doseof an effective amount of one or more compounds of the invention and adose of an effective amount of one or more therapies (e.g., one or moreprophylactic or therapeutic agents useful for the prevention, treatment,management, or amelioration of a proliferative disorder or a symptomthereof). The invention also provides methods for preventing, treating,managing, or ameliorating a proliferative disorder or a symptom thereofby administering one or more compounds of the invention in combinationwith any other therapy(ies) to patients who have proven refractory toother therapies but are no longer on these therapies.

The compounds of the invention and/or other therapies can beadministered to a subject by any route known to one of skill in the art.Examples of routes of administration include, but are not limited to,parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g.,inhalation), intranasal, transdermal (topical), transmucosal, and rectaladministration.

Agents Useful In Combination with Compounds of the Invention

Anticancer agents that can be co-administered with the compounds of theinvention include Taxol™, also referred to as “paclitaxel”, which is awell-known anti-cancer drug which acts by enhancing and stabilizingmicrotubule formation, and analogs of Taxol™, such as Taxotere™.Compounds that have the basic taxane skeleton as a common structurefeature, have also been shown to have the ability to arrest cells in theG2-M phases due to stabilized microtubules and may be useful fortreating cancer in combination with the compounds of the invention.

Other anti-cancer agents that can be employed in combination with thecompounds of the invention include Adriamycin, Dactinomycin, Bleomycin,Vinblastine, Cisplatin, acivicin; aclarubicin; acodazole hydrochloride;acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantroneacetate; aminoglutethimide; amsacrine; anastrozole; anthramycin;asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat;benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate;bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan;cactinomycin; calusterone; caracemide; carbetimer; carboplatin;carmustine; carubicin hydrochloride; carzelesin; cedefingol;chlorambucil; cirolemycin; cladribine; crisnatol mesylate;cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride;decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate;diaziquone; doxorubicin; doxorubicin hydrochloride; droloxifene;droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate;eflornithine hydrochloride; elsamitrucin; enloplatin; enpromate;epipropidine; epirubicin hydrochloride; erbulozole; esorubicinhydrochloride; estramustine; estramustine phosphate sodium; etanidazole;etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride;fazarabine; fenretinide; floxuridine; fludarabine phosphate;fluorouracil; fluorocitabine; fosquidone; fostriecin sodium;gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicinhydrochloride; ifosfamide; ilmofosine; interleukin II (includingrecombinant interleukin II, or rIL2), interferon alfa-2a; interferonalfa-2b; interferon alfa-n1; interferon alfa-n3; interferon beta-I a;interferon gamma-I b; iproplatin; irinotecan hydrochloride; lanreotideacetate; letrozole; leuprolide acetate; liarozole hydrochloride;lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol;maytansine; mechlorethamine hydrochloride; megestrol acetate;melengestrol acetate; melphalan; menogaril; mercaptopurine;methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide;mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper;mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole;nogalamycin; ormaplatin; oxisuran; pegaspargase; peliomycin;pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan;piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium;porfiromycin; prednimustine; procarbazine hydrochloride; puromycin;puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safingol;safingol hydrochloride; semustine; simtrazene; sparfosate sodium;sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin;streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium;tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone;testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin;tirapazamine; toremifene citrate; trestolone acetate; triciribinephosphate; trimetrexate; trimetrexate glucuronate; triptorelin;tubulozole hydrochloride; uracil mustard; uredepa; vapreotide;verteporfin; vinblastine sulfate; vincristine sulfate; vindesine;vindesine sulfate; vinepidine sulfate; vinglycinate sulfate;vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate;vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicinhydrochloride.

Other anti-cancer drugs that can be employed in combination with thecompounds of the invention include: 20-epi-1,25 dihydroxyvitamin D3;5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol;adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine;amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine;anagrelide; anastrozole; andrographolide; angiogenesis inhibitors;antagonist D; antagonist G; antarelix; anti-dorsalizing morphogeneticprotein-1; antiandrogen, prostatic carcinoma; antiestrogen;antineoplaston; antisense oligonucleotides; aphidicolin glycinate;apoptosis gene modulators; apoptosis regulators; apurinic acid;ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane;atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron;azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat;BCR/ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactamderivatives; beta-alethine; betaclamycin B; betulinic acid; bFGFinhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide;bistratene A; bizelesin; breflate; bropirimine; budotitane; buthioninesulfoximine; calcipotriol; calphostin C; camptothecin derivatives;canarypox IL-2; capecitabine; carboxamide-amino-triazole;carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor;carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropinB; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost;cis-porphyrin; cladribine; clomifene analogues; clotrimazole;collismycin A; collismycin B; combretastatin A4; combretastatinanalogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8;cryptophycin A derivatives; curacin A; cyclopentanthraquinones;cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor;cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin;dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone;didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine;9-dioxamycin; diphenyl spiromustine; docosanol; dolasetron;doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen;ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur;epirubicin; epristeride; estramustine analogue; estrogen agonists;estrogen antagonists; etanidazole; etoposide phosphate; exemestane;fadrozole; fazarabine; fenretinide; filgrastim; finasteride;flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicinhydrochloride; forfenimex; formestane; fostriecin; fotemustine;gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix;gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam;heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid;idarubicin; idoxifene; idramantone; ilmofosine; ilomastat;imidazoacridones; imiquimod; immunostimulant peptides; insulin-likegrowth factor-1 receptor inhibitor; interferon agonists; interferons;interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact;irsogladine; isobengazole; isohomohalicondrin B; itasetron;jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide;leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole;leukemia inhibiting factor; leukocyte alpha interferon;leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole;linear polyamine analogue; lipophilic disaccharide peptide; lipophilicplatinum compounds; lissoclinamide 7; lobaplatin; lombricine;lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine;lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides;maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysininhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone;meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone;miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone;mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growthfactor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonalantibody, human chorionic gonadotrophin; monophosphoryl lipidA+myobacterium cell wall sk; mopidamol; multiple drug resistance geneinhibitor; multiple tumor suppressor 1-based therapy; mustard anticanceragent; mycaperoxide B; mycobacterial cell wall extract; myriaporone;N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip;naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin;nemorubicin; neridronic acid; neutral endopeptidase; nilutamide;nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn;06-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone;ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin;osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin;pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine;pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin;pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin;phenylacetate; phosphatase inhibitors; picibanil; pilocarpinehydrochloride; pirarubicin; piritrexim; placetin A; placetin B;plasminogen activator inhibitor; platinum complex; platinum compounds;platinum-triamine complex; porfimer sodium; porfiromycin; prednisone;propyl bis-acridone; prostaglandin J2; proteasome inhibitors; proteinA-based immune modulator; protein kinase C inhibitor; protein kinase Cinhibitors, microalgal; protein tyrosine phosphatase inhibitors; purinenucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine;pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists;raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors;ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide;rohitukine; romurtide; roquinimex; rubiginone B1; ruboxyl; safingol;saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics;semustine; senescence derived inhibitor 1; sense oligonucleotides;signal transduction inhibitors; signal transduction modulators; singlechain antigen-binding protein; sizofiran; sobuzoxane; sodiumborocaptate; sodium phenylacetate; solverol; somatomedin bindingprotein; sonermin; sparfosic acid; spicamycin D; spiromustine;splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-celldivision inhibitors; stipiamide; stromelysin inhibitors; sulfinosine;superactive vasoactive intestinal peptide antagonist; suradista;suramin; swainsonine; synthetic glycosaminoglycans; tallimustine;tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium;tegafur; tellurapyrylium; telomerase inhibitors; temoporfin;temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine;thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic;thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroidstimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocenebichloride; topsentin; toremifene; totipotent stem cell factor;translation inhibitors; tretinoin; triacetyluridine; triciribine;trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinaseinhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenitalsinus-derived growth inhibitory factor; urokinase receptor antagonists;vapreotide; variolin B; vector system, erythrocyte gene therapy;velaresol; veramine; verdins; verteporf in; vinorelbine; vinxaltine;vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatinstimalamer. Preferred anti-cancer drugs are 5-fluorouracil andleucovorin.

Other chemotherapeutic agents that can be employed in combination withthe compounds of the invention include but are not limited to alkylatingagents, antimetabolites, natural products, or hormones. Examples ofalkylating agents useful for the treatment or prevention of T-cellmalignancies in the methods and compositions of the invention includebut are not limited to, nitrogen mustards (e.g., mechloroethamine,cyclophosphamide, chlorambucil, etc.), alkyl sulfonates (e.g.,busulfan), nitrosoureas (e.g., carmustine, lomusitne, etc.), ortriazenes (decarbazine, etc.). Examples of antimetabolites useful forthe treatment or prevention of T-cell malignancies in the methods andcompositions of the invention include but are not limited to folic acidanalog (e.g., methotrexate), or pyrimidine analogs (e.g., Cytarabine),purine analogs (e.g., mercaptopurine, thioguanine, pentostatin).Examples of natural products useful for the treatment or prevention ofT-cell malignancies in the methods and compositions of the inventioninclude but are not limited to vinca alkaloids (e.g., vinblastin,vincristine), epipodophyllotoxins (e.g., etoposide), antibiotics (e.g.,daunorubicin, doxorubicin, bleomycin), enzymes (e.g., L-asparaginase),or biological response modifiers (e.g., interferon alpha).

Examples of alkylating agents that can be employed in combination withthe compounds of the invention include but are not limited to, nitrogenmustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil,melphalan, etc.), ethylenimine and methylmelamines (e.g.,hexamethlymelamine, thiotepa), alkyl sulfonates (e.g., busulfan),nitrosoureas (e.g., carmustine, lomusitne, semustine, streptozocin,etc.), or triazenes (decarbazine, etc.). Examples of antimetabolitesuseful for the treatment or prevention of cancer in the methods andcompositions of the invention include but are not limited to folic acidanalog (e.g., methotrexate), or pyrimidine analogs (e.g., fluorouracil,floxouridine, Cytarabine), purine analogs (e.g., mercaptopurine,thioguanine, pentostatin). Examples of natural products useful for thetreatment or prevention of cancer in the methods and compositions of theinvention include but are not limited to vinca alkaloids (e.g.,vinblastin, vincristine), epipodophyllotoxins (e.g., etoposide,teniposide), antibiotics (e.g., actinomycin D, daunorubicin,doxorubicin, bleomycin, plicamycin, mitomycin), enzymes (e.g.,L-asparaginase), or biological response modifiers (e.g., interferonalpha). Examples of hormones and antagonists useful for the treatment orprevention of cancer in the methods and compositions of the inventioninclude but are not limited to adrenocorticosteroids (e.g., prednisone),progestins (e.g., hydroxyprogesterone caproate, megestrol acetate,medroxyprogesterone acetate), estrogens (e.g., diethlystilbestrol,ethinyl estradiol), antiestrogen (e.g., tamoxifen), androgens (e.g.,testosterone propionate, fluoxymesterone), antiandrogen (e.g.,flutamide), gonadotropin releasing hormone analog (e.g., leuprolide).Other agents that can be used in the methods and compositions of theinvention for the treatment or prevention of cancer include platinumcoordination complexes (e.g., cisplatin, carboblatin), anthracenedione(e.g., mitoxantrone), substituted urea (e.g., hydroxyurea), methylhydrazine derivative (e.g., procarbazine), adrenocortical suppressant(e.g., mitotane, aminoglutethimide).

Examples of anti-cancer agents which act by arresting cells in the G2-Mphases due to stabilized microtubules and which can be used incombination with the compounds of the invention include withoutlimitation the following marketed drugs and drugs in development:Erbulozole (also known as R-55104), Dolastatin 10 (also known as DLS-10and NSC-376128), Mivobulin isethionate (also known as CI-980),Vincristine, NSC-639829, Discodermolide (also known as NVP-XX-A-296),ABT-751 (Abbott, also known as E-7010), Altorhyrtins (such asAltorhyrtin A and Altorhyrtin C), Spongistatins (such as Spongistatin 1,Spongistatin 2, Spongistatin 3, Spongistatin 4, Spongistatin 5,Spongistatin 6, Spongistatin 7, Spongistatin 8, and Spongistatin 9),Cemadotin hydrochloride (also known as LU-103793 and NSC-D-669356),Epothilones (such as Epothilone A, Epothilone B, Epothilone C (alsoknown as desoxyepothilone A or dEpoA), Epothilone D (also referred to asKOS-862, dEpoB, and desoxyepothilone B), Epothilone E, Epothilone F,Epothilone B N-oxide, Epothilone A N-oxide, 16-aza-epothilone B,21-aminoepothilone B (also known as BMS-310705), 21-hydroxyepothilone D(also known as Desoxyepothilone F and dEpoF), 26-fluoroepothilone),Auristatin PE (also known as NSC-654663), Soblidotin (also known asTZT-1027), LS-4559-P (Pharmacia, also known as LS-4577), LS-4578(Pharmacia, also known as LS-477-P), LS-4477 (Pharmacia), LS-4559(Pharmacia), RPR-112378 (Aventis), Vincristine sulfate, DZ-3358(Daiichi), FR-182877 (Fujisawa, also known as WS-9885B), GS-164(Takeda), GS-198 (Takeda), KAR-2 (Hungarian Academy of Sciences),BSF-223651 (BASF, also known as ILX-651 and LU-223651), SAH-49960(Lilly/Novartis), SDZ-268970 (Lilly/Novartis), AM-97 (Armad/KyowaHakko), AM-132 (Armad), AM-138 (Armad/Kyowa Hakko), IDN-5005 (Indena),Cryptophycin 52 (also known as LY-355703), AC-7739 (Ajinomoto, alsoknown as AVE-8063A and CS-39.HCl), AC-7700 (Ajinomoto, also known asAVE-8062, AVE-8062A, CS-39-L-Ser.HCl, and RPR-258062A), Vitilevuamide,Tubulysin A, Canadensol, Centaureidin (also known as NSC-106969),T-138067 (Tularik, also known as T-67, TL-138067 and TI-138067), COBRA-1(Parker Hughes Institute, also known as DDE-261 and WHI-261), H10(Kansas State University), H16 (Kansas State University), Oncocidin A1(also known as BTO-956 and DIME), DDE-313 (Parker Hughes Institute),Fijianolide B, Laulimalide, SPA-2 (Parker Hughes Institute), SPA-1(Parker Hughes Institute, also known as SPIKET-P), 3-IAABU(Cytoskeleton/Mt. Sinai School of Medicine, also known as MF-569),Narcosine (also known as NSC-5366), Nascapine, D-24851 (Asta Medica),A-105972 (Abbott), Hemiasterlin, 3-BAABU (Cytoskeleton/Mt. Sinai Schoolof Medicine, also known as MF-191), TMPN (Arizona State University),Vanadocene acetylacetonate, T-138026 (Tularik), Monsatrol, Inanocine(also known as NSC-698666), 3-IAABE (Cytoskeleton/Mt. Sinai School ofMedicine), A-204197 (Abbott), T-607 (Tularik, also known as T-900607),RPR-115781 (Aventis), Eleutherobins (such as Desmethyleleutherobin,Desaetyleleutherobin, Isoeleutherobin A, and Z-Eleutherobin),Caribaeoside, Caribaeolin, Halichondrin B, D-64131 (Asta Medica),D-68144 (Asta Medica), Diazonamide A, A-293620 (Abbott), NPI-2350(Nereus), Taccalonolide A, TUB-245 (Aventis), A-259754 (Abbott),Diozostatin, (−)-Phenylahistin (also known as NSCL-96F037), D-68838(Asta Medica), D-68836 (Asta Medica), Myoseverin B, D-43411 (Zentaris,also known as D-81862), A-289099 (Abbott), A-318315 (Abbott), HTI-286(also known as SPA-110, trifluoroacetate salt) (Wyeth), D-82317(Zentaris), D-82318 (Zentaris), SC-12983 (NCl), Resverastatin phosphatesodium, BPR-0Y-007 (National Health Research Institutes), and SSR-250411(Sanofi).

Pharmaceutical Compositions

The present invention provides compositions for the treatment,prophylaxis, and amelioration of proliferative disorders, such ascancer. In a specific embodiment, a composition comprises one or morecompounds of the invention, or a pharmaceutically acceptable salt,solvate, clathrate, hydrate or prodrug thereof. In another embodiment, acomposition of the invention comprises one or more prophylactic ortherapeutic agents other than a compound of the invention, or apharmaceutically acceptable salt, solvate, clathrate, hydrate, prodrugthereof. In another embodiment, a composition of the invention comprisesone or more compounds of the invention, or a pharmaceutically acceptablesalt, solvate, clathrate, hydrate or prodrug thereof, and one or moreother prophylactic or therapeutic agents. In another embodiment, thecomposition comprises a compound of the invention, or a pharmaceuticallyacceptable salt, solvate, clathrate, hydrate, or prodrug thereof, and apharmaceutically acceptable carrier, diluent or excipient.

In a preferred embodiment, a composition of the invention is apharmaceutical composition or a single unit dosage form. Pharmaceuticalcompositions and dosage forms of the invention comprise one or moreactive ingredients in relative amounts and formulated in such a way thata given pharmaceutical composition or dosage form can be used to treator prevent proliferative disorders, such as cancer. Preferredpharmaceutical compositions and dosage forms comprise a compound offormulas (I) through (X), (IA) through (XA), (IB) through (XB), or ofTable 1, or a pharmaceutically acceptable prodrug, salt, solvate,clathrate, hydrate, or prodrug thereof, optionally in combination withone or more additional active agents.

A pharmaceutical composition of the invention is formulated to becompatible with its intended route of administration. Examples of routesof administration include, but are not limited to, parenteral, e.g.,intravenous, intradermal, subcutaneous, oral (e.g., inhalation),intranasal, transdermal (topical), transmucosal, and rectaladministration. In a specific embodiment, the composition is formulatedin accordance with routine procedures as a pharmaceutical compositionadapted for intravenous, subcutaneous, intramuscular, oral, intranasalor topical administration to human beings. In a preferred embodiment, apharmaceutical composition is formulated in accordance with routineprocedures for subcutaneous administration to human beings.

Single unit dosage forms of the invention are suitable for oral, mucosal(e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g.,subcutaneous, intravenous, bolus injection, intramuscular, orintraarterial), or transdermal administration to a patient. Examples ofdosage forms include, but are not limited to: tablets; caplets;capsules, such as soft elastic gelatin capsules; cachets; troches;lozenges; dispersions; suppositories; ointments; cataplasms (poultices);pastes; powders; dressings; creams; plasters; solutions; patches;aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage formssuitable for oral or mucosal administration to a patient, includingsuspensions (e.g., aqueous or non-aqueous liquid suspensions,oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions,and elixirs; liquid dosage forms suitable for parenteral administrationto a patient; and sterile solids (e.g., crystalline or amorphous solids)that can be reconstituted to provide liquid dosage forms suitable forparenteral administration to a patient.

The composition, shape, and type of dosage forms of the invention willtypically vary depending on their use. For example, a dosage formsuitable for mucosal administration may contain a smaller amount ofactive ingredient(s) than an oral dosage form used to treat the sameindication. This aspect of the invention will be readily apparent tothose skilled in the art. See, e.g., Remington's Pharmaceutical Sciences(1990) 18th ed., Mack Publishing, Easton Pa.

Typical pharmaceutical compositions and dosage forms comprise one ormore excipients. Suitable excipients are well known to those skilled inthe art of pharmacy, and non-limiting examples of suitable excipientsare provided herein. Whether a particular excipient is suitable forincorporation into a pharmaceutical composition or dosage form dependson a variety of factors well known in the art including, but not limitedto, the way in which the dosage form will be administered to a patient.For example, oral dosage forms such as tablets may contain excipientsnot suited for use in parenteral dosage forms.

The suitability of a particular excipient may also depend on thespecific active ingredients in the dosage form. For example, thedecomposition of some active ingredients can be accelerated by someexcipients such as lactose, or when exposed to water. Active ingredientsthat comprise primary or secondary amines (e.g., N-desmethylvenlafaxineand N,N-didesmethylvenlafaxine) are particularly susceptible to suchaccelerated decomposition. Consequently, this invention encompassespharmaceutical compositions and dosage forms that contain little, ifany, lactose. As used herein, the term “lactose-free” means that theamount of lactose present, if any, is insufficient to substantiallyincrease the degradation rate of an active ingredient. Lactose-freecompositions of the invention can comprise excipients that are wellknown in the art and are listed, for example, in the U.S. Pharmocopia(USP)SP(XXI)/NF (XVI). In general, lactose-free compositions compriseactive ingredients, a binder/filler, and a lubricant in pharmaceuticallycompatible and pharmaceutically acceptable amounts. Preferredlactose-free dosage forms comprise active ingredients, microcrystallinecellulose, pre-gelatinized starch, and magnesium stearate.

This invention further encompasses anhydrous pharmaceutical compositionsand dosage forms comprising active ingredients, since water canfacilitate the degradation of some compounds. For example, the additionof water (e.g., 5%) is widely accepted in the pharmaceutical arts as ameans of simulating long-term storage in order to determinecharacteristics such as shelf-life or the stability of formulations overtime. See, e.g., Jens T. Carstensen (1995) Drug Stability: Principles &Practice, 2d. Ed., Marcel Dekker, NY, N.Y., 379-80. In effect, water andheat accelerate the decomposition of some compounds. Thus, the effect ofwater on a formulation can be of great significance since moistureand/or humidity are commonly encountered during manufacture, handling,packaging, storage, shipment, and use of formulations.

Anhydrous pharmaceutical compositions and dosage forms of the inventioncan be prepared using anhydrous or low moisture containing ingredientsand low moisture or low humidity conditions. Pharmaceutical compositionsand dosage forms that comprise lactose and at least one activeingredient that comprises a primary or secondary amine are preferablyanhydrous if substantial contact with moisture and/or humidity duringmanufacturing, packaging, and/or storage is expected.

An anhydrous pharmaceutical composition should be prepared and storedsuch that its anhydrous nature is maintained. Accordingly, anhydrouscompositions are preferably packaged using materials known to preventexposure to water such that they can be included in suitable formularykits. Examples of suitable packaging include, but are not limited to,hermetically sealed foils, plastics, unit dose containers (e.g., vials),blister packs, and strip packs.

The invention further encompasses pharmaceutical compositions and dosageforms that comprise one or more compounds that reduce the rate by whichan active ingredient will decompose. Such compounds, which are referredto herein as “stabilizer” include, but are not limited to, antioxidantssuch as ascorbic acid, pH buffers, or salt buffers.

Oral Dosage Forms

Pharmaceutical compositions of the invention that are suitable for oraladministration can be presented as discrete dosage forms, such as, butare not limited to, tablets (e.g., chewable tablets), caplets, capsules,and liquids (e.g., flavored syrups). Such dosage forms containpredetermined amounts of active ingredients, and may be prepared bymethods of pharmacy well known to those skilled in the art. Seegenerally, Remington's Pharmaceutical Sciences (1990) 18th ed., MackPublishing, Easton Pa.

Typical oral dosage forms of the invention are prepared by combining theactive ingredient(s) in an admixture with at least one excipientaccording to conventional pharmaceutical compounding techniques.Excipients can take a wide variety of forms depending on the form ofpreparation desired for administration. For example, excipients suitablefor use in oral liquid or aerosol dosage forms include, but are notlimited to, water, glycols, oils, alcohols, flavoring agents,preservatives, and coloring agents. Examples of excipients suitable foruse in solid oral dosage forms (e.g., powders, tablets, capsules, andcaplets) include, but are not limited to, starches, sugars,micro-crystalline cellulose, diluents, granulating agents, lubricants,binders, and disintegrating agents.

Because of their ease of administration, tablets and capsules representthe most advantageous oral dosage unit forms, in which case solidexcipients are employed. If desired, tablets can be coated by standardaqueous or nonaqueous techniques. Such dosage forms can be prepared byany of the methods of pharmacy. In general, pharmaceutical compositionsand dosage forms are prepared by uniformly and intimately admixing theactive ingredients with liquid carriers, finely divided solid carriers,or both, and then shaping the product into the desired presentation ifnecessary.

For example, a tablet can be prepared by compression or molding.Compressed tablets can be prepared by compressing in a suitable machinethe active ingredients in a free-flowing form such as powder orgranules, optionally mixed with an excipient. Molded tablets can be madeby molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

Examples of excipients that can be used in oral dosage forms of theinvention include, but are not limited to, binders, fillers,disintegrants, and lubricants. Binders suitable for use inpharmaceutical compositions and dosage forms include, but are notlimited to, corn starch, potato starch, or other starches, gelatin,natural and synthetic gums such as acacia, sodium alginate, alginicacid, other alginates, powdered tragacanth, guar gum, cellulose and itsderivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethylcellulose calcium, sodium carboxymethyl cellulose), polyvinylpyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropylmethyl cellulose, (e.g., Nos. 2208, 2906, 2910), microcrystallinecellulose, and mixtures thereof.

Suitable forms of microcrystalline cellulose include, but are notlimited to, the materials sold as AVICEL-PH-101, AVICEL-PH-103 AVICELRC-581, AVICEL-PH-105 (available from FMC Corporation, American ViscoseDivision, Avicel Sales, Marcus Hook, Pa.), and mixtures thereof. Onespecific binder is a mixture of microcrystalline cellulose and sodiumcarboxymethyl cellulose sold as AVICEL RC-581. Suitable anhydrous or lowmoisture excipients or additives include AVICEL-PH-103J and Starch 1500LM.

Examples of fillers suitable for use in the pharmaceutical compositionsand dosage forms disclosed herein include, but are not limited to, talc,calcium carbonate (e.g., granules or powder), microcrystallinecellulose, powdered cellulose, dextrates, kaolin, mannitol, silicicacid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.The binder or filler in pharmaceutical compositions of the invention istypically present in from about 50 to about 99 weight percent of thepharmaceutical composition or dosage form.

Disintegrants are used in the compositions of the invention to providetablets that disintegrate when exposed to an aqueous environment.Tablets that contain too much disintegrant may disintegrate in storage,while those that contain too little may not disintegrate at a desiredrate or under the desired conditions. Thus, a sufficient amount ofdisintegrant that is neither too much nor too little to detrimentallyalter the release of the active ingredients should be used to form solidoral dosage forms of the invention. The amount of disintegrant usedvaries based upon the type of formulation, and is readily discernible tothose of ordinary skill in the art. Typical pharmaceutical compositionscomprise from about 0.5 to about 15 weight percent of disintegrant,preferably from about 1 to about 5 weight percent of disintegrant.

Disintegrants that can be used in pharmaceutical compositions and dosageforms of the invention include, but are not limited to, agar-agar,alginic acid, calcium carbonate, microcrystalline cellulose,croscarmellose sodium, crospovidone, polacrilin potassium, sodium starchglycolate, potato or tapioca starch, other starches, pre-gelatinizedstarch, other starches, clays, other algins, other celluloses, gums, andmixtures thereof.

Lubricants that can be used in pharmaceutical compositions and dosageforms of the invention include, but are not limited to, calciumstearate, magnesium stearate, mineral oil, light mineral oil, glycerin,sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid,sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanutoil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, andsoybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, andmixtures thereof. Additional lubricants include, for example, a syloidsilica gel (AEROSIL 200, manufactured by W.R. Grace Co. of Baltimore,Md.), a coagulated aerosol of synthetic silica (marketed by Degussa Co.of Plano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide product sold byCabot Co. of Boston, Mass.), and mixtures thereof. If used at all,lubricants are typically used in an amount of less than about 1 weightpercent of the pharmaceutical compositions or dosage forms into whichthey are incorporated.

Controlled Release Dosage Forms

Active ingredients of the invention can be administered by controlledrelease means or by delivery devices that are well known to those ofordinary skill in the art. Examples include, but are not limited to,those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809;3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548,5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of which isincorporated herein by reference. Such dosage forms can be used toprovide slow or controlled-release of one or more active ingredientsusing, for example, hydropropylmethyl cellulose, other polymer matrices,gels, permeable membranes, osmotic systems, multilayer coatings,microparticles, liposomes, microspheres, or a combination thereof toprovide the desired release profile in varying proportions. Suitablecontrolled-release formulations known to those of ordinary skill in theart, including those described herein, can be readily selected for usewith the active ingredients of the invention. The invention thusencompasses single unit dosage forms suitable for oral administrationsuch as, but not limited to, tablets, capsules, gelcaps, and capletsthat are adapted for controlled-release.

All controlled-release pharmaceutical products have a common goal ofimproving drug therapy over that achieved by their non-controlledcounterparts. Ideally, the use of an optimally designedcontrolled-release preparation in medical treatment is characterized bya minimum of drug substance being employed to cure or control thecondition in a minimum amount of time. Advantages of controlled-releaseformulations include extended activity of the drug, reduced dosagefrequency, and increased patient compliance.

Most controlled-release formulations are designed to initially releasean amount of drug (active ingredient) that promptly produces the desiredtherapeutic effect, and gradually and continually release of otheramounts of drug to maintain this level of therapeutic or prophylacticeffect over an extended period of time. In order to maintain thisconstant level of drug in the body, the drug must be released from thedosage form at a rate that will replace the amount of drug beingmetabolized and excreted from the body. Controlled-release of an activeingredient can be stimulated by various conditions including, but notlimited to, pH, temperature, enzymes, water, or other physiologicalconditions or compounds.

A particular extended release formulation of this invention comprises atherapeutically or prophylactically effective amount of a compound offormulas (I) through (X), (IA) through (XA), (IB) through (XB), or ofTable 1, or a pharmaceutically acceptable salt, solvate, hydrate,clathrate, or prodrug thereof, in spheroids which further comprisemicrocrystalline cellulose and, optionally,hydroxypropylmethyl-cellulose coated with a mixture of ethyl celluloseand hydroxypropylmethylcellulose. Such extended release formulations canbe prepared according to U.S. Pat. No. 6,274,171, the entirely of whichis incorporated herein by reference.

A specific controlled-release formulation of this invention comprisesfrom about 6% to about 40% a compound of formulas (I) through (X), (IA)through (XA), (IB) through (XB), or of Table 1, or a pharmaceuticallyacceptable salt, solvate, hydrate, clathrate, or prodrug thereof, byweight, about 50% to about 94% microcrystalline cellulose, NF, byweight, and optionally from about 0.25% to about 1% by weight ofhydroxypropyl-methylcellulose, USP, wherein the spheroids are coatedwith a film coating composition comprised of ethyl cellulose andhydroxypropylmethylcellulose.

Parenteral Dosage Forms

Parenteral dosage forms can be administered to patients by variousroutes including, but not limited to, subcutaneous, intravenous(including bolus injection), intramuscular, and intraarterial. Becausetheir administration typically bypasses patients' natural defensesagainst contaminants, parenteral dosage forms are preferably sterile orcapable of being sterilized prior to administration to a patient.Examples of parenteral dosage forms include, but are not limited to,solutions ready for injection, dry products ready to be dissolved orsuspended in a pharmaceutically acceptable vehicle for injection,suspensions ready for injection, and emulsions.

Suitable vehicles that can be used to provide parenteral dosage forms ofthe invention are well known to those skilled in the art. Examplesinclude, but are not limited to: Water for Injection USP; aqueousvehicles such as, but not limited to, Sodium Chloride Injection,Ringer's Injection, Dextrose Injection, Dextrose and Sodium ChlorideInjection, and Lactated Ringer's Injection; water-miscible vehicles suchas, but not limited to, ethyl alcohol, polyethylene glycol, andpolypropylene glycol; and non-aqueous vehicles such as, but not limitedto, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate,isopropyl myristate, and benzyl benzoate.

Compounds that increase the solubility of one or more of the activeingredients disclosed herein can also be incorporated into theparenteral dosage forms of the invention.

Transdermal, Topical, and Mucosal Dosage Forms

Transdermal, topical, and mucosal dosage forms of the invention include,but are not limited to, ophthalmic solutions, sprays, aerosols, creams,lotions, ointments, gels, solutions, emulsions, suspensions, or otherforms known to one of skill in the art. See, e.g., Remington'sPharmaceutical Sciences (1980 & 1990) 16th and 18th eds., MackPublishing, Easton Pa. and Introduction to Pharmaceutical Dosage Forms(1985) 4th ed., Lea & Febiger, Philadelphia. Dosage forms suitable fortreating mucosal tissues within the oral cavity can be formulated asmouthwashes or as oral gels. Further, transdermal dosage forms include“reservoir type” or “matrix type” patches, which can be applied to theskin and worn for a specific period of time to permit the penetration ofa desired amount of active ingredients.

Suitable excipients (e.g., carriers and diluents) and other materialsthat can be used to provide transdermal, topical, and mucosal dosageforms encompassed by this invention are well known to those skilled inthe pharmaceutical arts, and depend on the particular tissue to which agiven pharmaceutical composition or dosage form will be applied. Withthat fact in mind, typical excipients include, but are not limited to,water, acetone, ethanol, ethylene glycol, propylene glycol,butane-1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil,and mixtures thereof to form lotions, tinctures, creams, emulsions, gelsor ointments, which are non-toxic and pharmaceutically acceptable.Moisturizers or humectants can also be added to pharmaceuticalcompositions and dosage forms if desired. Examples of such additionalingredients are well known in the art. See, e.g., Remington'sPharmaceutical Sciences (1980 & 1990) 16th and 18th eds., MackPublishing, Easton Pa.

Depending on the specific tissue to be treated, additional componentsmay be used prior to, in conjunction with, or subsequent to treatmentwith active ingredients of the invention. For example, penetrationenhancers can be used to assist in delivering the active ingredients tothe tissue. Suitable penetration enhancers include, but are not limitedto: acetone; various alcohols such as ethanol, oleyl, andtetrahydrofuryl; alkyl sulfoxides such as dimethyl sulfoxide; dimethylacetamide; dimethyl formamide; polyethylene glycol; pyrrolidones such aspolyvinylpyrrolidone; Kollidon grades (Povidone, Polyvidone); urea; andvarious water-soluble or insoluble sugar esters such as Tween 80(polysorbate 80) and Span 60 (sorbitan monostearate).

The pH of a pharmaceutical composition or dosage form, or of the tissueto which the pharmaceutical composition or dosage form is applied, mayalso be adjusted to improve delivery of one or more active ingredients.Similarly, the polarity of a solvent carrier, its ionic strength, ortonicity can be adjusted to improve delivery. Compounds such asstearates can also be added to pharmaceutical compositions or dosageforms to advantageously alter the hydrophilicity or lipophilicity of oneor more active ingredients so as to improve delivery. In this regard,stearates can serve as a lipid vehicle for the formulation, as anemulsifying agent or surfactant, and as a delivery-enhancing orpenetration-enhancing agent. Different salts, hydrates or solvates ofthe active ingredients can be used to further adjust the properties ofthe resulting composition.

Dosage & Frequency of Administration

The amount of the compound or composition of the invention which will beeffective in the prevention, treatment, management, or amelioration of aproliferative disorders, such as cancer, or one or more symptomsthereof, will vary with the nature and severity of the disease orcondition, and the route by which the active ingredient is administered.The frequency and dosage will also vary according to factors specificfor each patient depending on the specific therapy (e.g., therapeutic orprophylactic agents) administered, the severity of the disorder,disease, or condition, the route of administration, as well as age,body, weight, response, and the past medical history of the patient.Effective doses may be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems. Suitable regiments can beselected by one skilled in the art by considering such factors and byfollowing, for example, dosages reported in the literature andrecommended in the Physician's Desk Reference (57th ed., 2003).

Exemplary doses of a small molecule include milligram or microgramamounts of the small molecule per kilogram of subject or sample weight(e.g., about 1 microgram per kilogram to about 500 milligrams perkilogram, about 100 micrograms per kilogram to about 5 milligrams perkilogram, or about 1 microgram per kilogram to about 50 micrograms perkilogram).

In general, the recommended daily dose range of a compound of theinvention for the conditions described herein lie within the range offrom about 0.01 mg to about 1000 mg per day, given as a singleonce-a-day dose or preferably as divided doses throughout a day. In oneembodiment, the daily dose is administered twice daily in equallydivided doses. Specifically, a daily dose range should be from about 5mg to about 500 mg per day, more specifically, between about 10 mg andabout 200 mg per day. In managing the patient, the therapy should beinitiated at a lower dose, perhaps about 1 mg to about 25 mg, andincreased if necessary up to about 200 mg to about 1000 mg per day aseither a single dose or divided doses, depending on the patient's globalresponse. It may be necessary to use dosages of the active ingredientoutside the ranges disclosed herein in some cases, as will be apparentto those of ordinary skill in the art. Furthermore, it is noted that theclinician or treating physician will know how and when to interrupt,adjust, or terminate therapy in conjunction with individual patientresponse.

Different therapeutically effective amounts may be applicable fordifferent proliferative disorders, as will be readily known by those ofordinary skill in the art. Similarly, amounts sufficient to prevent,manage, treat or ameliorate such proliferative disorders, butinsufficient to cause, or sufficient to reduce, adverse effectsassociated with the compounds of the invention are also encompassed bythe above described dosage amounts and dose frequency schedules.Further, when a patient is administered multiple dosages of a compoundof the invention, not all of the dosages need be the same. For example,the dosage administered to the patient may be increased to improve theprophylactic or therapeutic effect of the compound or it may bedecreased to reduce one or more side effects that a particular patientis experiencing.

In a specific embodiment, the dosage of the composition of the inventionor a compound of the invention administered to prevent, treat, manage,or ameliorate a proliferative disorders, such as cancer, or one or moresymptoms thereof in a patient is 150 μg/kg, preferably 250 μg/kg, 500μg/kg, 1 mg/kg, 5 mg/kg, 10 mg/kg, 25 mg/kg, 50 mg/kg, 75 mg/kg, 100mg/kg, 125 mg/kg, 150 mg/kg, or 200 mg/kg or more of a patient's bodyweight. In another embodiment, the dosage of the composition of theinvention or a compound of the invention administered to prevent, treat,manage, or ameliorate a proliferative disorders, such as cancer, or oneor more symptoms thereof in a patient is a unit dose of 0.1 mg to 20 mg,0.1 mg to 15 mg, 0.1 mg to 12 mg, 0.1 mg to 10 mg, 0.1 mg to 8 mg, 0.1mg to 7 mg, 0.1 mg to 5 mg, 0.1 to 2.5 mg, 0.25 mg to 20 mg, 0.25 to 15mg, 0.25 to 12 mg, 0.25 to 10 mg, 0.25 to 8 mg, 0.25 mg to 7 mg, 0.25 mgto 5 mg, 0.5 mg to 2.5 mg, 1 mg to 20 mg, 1 mg to 15 mg, 1 mg to 12 mg,1 mg to 10 mg, 1 mg to 8 mg, 1 mg to 7 mg, 1 mg to 5 mg, or 1 mg to 2.5mg.

The dosages of prophylactic or therapeutic agents other than compoundsof the invention, which have been or are currently being used toprevent, treat, manage, or proliferative disorders, such as cancer, orone or more symptoms thereof can be used in the combination therapies ofthe invention. Preferably, dosages lower than those which have been orare currently being used to prevent, treat, manage, or ameliorate aproliferative disorders, or one or more symptoms thereof, are used inthe combination therapies of the invention. The recommended dosages ofagents currently used for the prevention, treatment, management, oramelioration of a proliferative disorders, such as cancer, or one ormore symptoms thereof, can obtained from any reference in the artincluding, but not limited to, Hardman et al., eds., 1996, Goodman &Gilman's The Pharmacological Basis Of Basis Of Therapeutics 9^(th) Ed,Mc-Graw-Hill, New York; Physician's Desk Reference (PDR) 57^(th) f Ed.,2003, Medical Economics Co., Inc., Montvale, N.J., which areincorporated herein by reference in its entirety.

In certain embodiments, when the compounds of the invention areadministered in combination with another therapy, the therapies (e.g.,prophylactic or therapeutic agents) are administered less than 5 minutesapart, less than 30 minutes apart, 1 hour apart, at about 1 hour apart,at about 1 to about 2 hours apart, at about 2 hours to about 3 hoursapart, at about 3 hours to about 4 hours apart, at about 4 hours toabout 5 hours apart, at about 5 hours to about 6 hours apart, at about 6hours to about 7 hours apart, at about 7 hours to about 8 hours apart,at about 8 hours to about 9 hours apart, at about 9 hours to about 10hours apart, at about 10 hours to about 11 hours apart, at about 11hours to about 12 hours apart, at about 12 hours to 18 hours apart, 18hours to 24 hours apart, 24 hours to 36 hours apart, 36 hours to 48hours apart, 48 hours to 52 hours apart, 52 hours to 60 hours apart, 60hours to 72 hours apart, 72 hours to 84 hours apart, 84 hours to 96hours apart, or 96 hours to 120 hours part. In one embodiment, two ormore therapies (e.g., prophylactic or therapeutic agents) areadministered within the same patient visit.

In certain embodiments, one or more compounds of the invention and oneor more other the therapies (e.g., prophylactic or therapeutic agents)are cyclically administered. Cycling therapy involves the administrationof a first therapy (e.g., a first prophylactic or therapeutic agents)for a period of time, followed by the administration of a second therapy(e.g., a second prophylactic or therapeutic agents) for a period oftime, followed by the administration of a third therapy (e.g., a thirdprophylactic or therapeutic agents) for a period of time and so forth,and repeating this sequential administration, i.e., the cycle in orderto reduce the development of resistance to one of the agents, to avoidor reduce the side effects of one of the agents, and/or to improve theefficacy of the treatment.

In certain embodiments, administration of the same compound of theinvention may be repeated and the administrations may be separated by atleast 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days,2 months, 75 days, 3 months, or 6 months. In other embodiments,administration of the same prophylactic or therapeutic agent may berepeated and the administration may be separated by at least at least 1day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2months, 75 days, 3 months, or 6 months.

In a specific embodiment, the invention provides a method of preventing,treating, managing, or ameliorating a proliferative disorders, such ascancer, or one or more symptoms thereof, said methods comprisingadministering to a subject in need thereof a dose of at least 150 pg/kg,preferably at least 250 pg/kg, at least 500 pg/kg, at least 1 mg/kg, atleast 5 mg/kg, at least 10 mg/kg, at least 25 mg/kg, at least 50 mg/kg,at least 75 mg/kg, at least 100 mg/kg, at least 125 mg/kg, at least 150mg/kg, or at least 200 mg/kg or more of one or more compounds of theinvention once every day, preferably, once every 2 days, once every 3days, once every 4 days, once every 5 days, once every 6 days, onceevery 7 days, once every 8 days, once every 10 days, once every twoweeks, once every three weeks, or once a month.

Other Embodiments

The compounds of the invention may be used as research tools (forexample, to evaluate the mechanism of action of new drug agents, toisolate new drug discovery targets using affinity chromatography, asantigens in an ELISA or ELISA-like assay, or as standards in in vitro orin vivo assays). These and other uses and embodiments of the compoundsand compositions of this invention will be apparent to those of ordinaryskill in the art.

The invention is further defined by reference to the following examplesdescribing in detail the preparation of compounds of the invention. Itwill be apparent to those skilled in the art that many modifications,both to materials and methods, may be practiced without departing fromthe purpose and interest of this invention. The following examples areset forth to assist in understanding the invention and should not beconstrued as specifically limiting the invention described and claimedherein. Such variations of the invention, including the substitution ofall equivalents now known or later developed, which would be within thepurview of those skilled in the art, and changes in formulation or minorchanges in experimental design, are to be considered to fall within thescope of the invention incorporated herein.

EXAMPLES Experimental Rationale

Without wishing to be bound by theory, it is believed that the compoundsof this invention inhibit tubulin polymerization and/or targetvasculature and, therefore, can be used to inhibit undesirable cellularproliferation in disorders such as cancer. The examples that followdemonstrate these properties.

Materials and General Methods

Reagents and solvents used below can be obtained from commercial sourcessuch as Aldrich Chemical Co. (Milwaukee, Wis., USA). ¹H-NMR and ¹³C-NMRspectra were recorded on a Varian 300 MHz NMR spectrometer. Significantpeaks are tabulated in the order: δ (ppm): chemical shift, multiplicity(s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br s,broad singlet), coupling constant(s) in Hertz (Hz) and number ofprotons.

Example 1 Synthesis of Representative Exemplary Compounds of ThisInvention Compound 34-(4-Methoxy-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole (1) Synthesisof 3-(4-Methoxy-phenyl)-1-(3,4,5-trimethoxy-phenyl)-propenone

To a stirred solution of p-anislaldehyde (1.36 g, 10 mmol) and1-(3,4,5-trimethoxy-phenyl)-ethanone (2.1 g, 10 mmol) in ethyl alcohol(EtOH) (10 mL) was added a 50% solution of NaOH in H₂O (1 mL). After thereaction had proceeded to completion, volatile components were removedunder reduced pressure and the residue was taken up with ethyl acetate(EtOAc) (50 mL). The EtOAc layer was washed with H₂O (2×30 mL) and thendried with Na₂SO₄. After removal of EtOAc, the product was precipitatedout from EtOH/H₂O, Solid material collected by filtration and was washedby H₂O (20 mL) and 95% ethyl alcohol (10 mL). The product,3-(4-Methoxy-phenyl)-1-(3,4,5-trimethoxy-phenyl)-propenone (2.8 g, 85%yield), was obtained as a yellow solid. ¹H-NMR δ 3.85 (s, 3H), 3.90 (s,3H), 3.95 (s, 6H), 6.95 (d, 2H, J=8), 7.28 (s, 2H), 7.39 (d, 1H, J=15),7.65 (d, 2H, J=8), 7.85 (d, 1H, J=15)ppm.

(2) Synthesis of[3-(4-Methoxy-phenyl)-oxiranyl]-(3,4,5-trimethoxy-phenyl)-methanone

To a stirred solution of3-(4-Methoxy-phenyl)-1-(3,4,5-trimethoxy-phenyl)-propenone (1.64 g, 5mmol) and 1N NaOH (2.52 mL) in 95% EtOH (22 mL) was added a coldsolution of 30% H₂O₂ (0.77 mL) at room temperature. After 72 h stirring,the precipitated material was collected by filtration and washed with95% EtOH to afford[3-(4-methoxy-phenyl)-oxiranyl]-(3,4,5-trimethoxy-phenyl)-methanone as awhite solid (1.38 g, yield 80%). ¹H-NMR (CDCl₃) δ 3.81 (s, 3H), 3.92 (s,6H), 3.95 (s, 3H), 4.05 (d, 1H, J=2), 4.20 (1H, J=2), 6.95 (d, 2H, J=7),7.25-7.35 (m, 4H) ppm.

(3) Synthesis of4-(4-Methoxy-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole

To a stirred solution of[3-(4-methoxy-phenyl)-oxiranyl]-(3,4,5-trimethoxy-phenyl)-methanone (0.5g, 1.45 mmol) in dry ether (15 mL) was added BF₃.Et₂O (2.52 mL) slowly.After the addition, it was heated to reflux for 1 h. After the reactionmixture had cooled to room temperature, it was poured into ice-H₂O (100mL). The etheral layer was separated and the aqueous layer was extractedwith ether (10 mL×3). The combined ether layers were washed with H₂O (20mL×2) and concentrated to dryness. The residue was then transferred withEtOH (3 mL) to a flask suited for a microwave reactor, and hydroxylaminehydrochloride (0.32 g, 4.6 mmol) and pyridine (1 mL) were added. Themixture was heated and stirred in a microwave reactor at 130° C. for 30min. The reaction mixture was then cooled to room temperature and pouredinto ice-H₂O (20 mL). The solid material was collected and washed withH₂O. After preparative HPLC or repeated solvating gas chromatography(SGC) (hexane to 14% Hexane/EtOAc), the product4-(4-Methoxy-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole was obtainedas a light yellow solid. ¹H-NMR (CDCl₃) δ 3.70 (s, 6H), 3.82 (s, 3H),3.85 (s, 3H), 6.85 (s, 2H), 6.94 (d, 2H, J=8), 7.33 (d, 2H, J=8), 8.30(s, 1H) ppm; ESMS calcd for C₁₉H₁₉NO₅: 341.0; found: 342.0 (M+H⁺).

Compound 1 4-(4-Bromo-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole

Compound 1 was synthesized in a similar way as described for Compound 3.¹H-NMR (CDCl₃) δ 3.75 (s, 6H), 3.88 (s, 3H), 6.85 (s, 2H), 7.25 (d, 2H,J=8), 7.58 (d, 2H, J=8), 8.35 (s, 1H) ppm; ESMS calcd for C₁₈H₁₆BrNO₄:389.0; found: 390.0 (M+H⁺).

Compound 464-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole

Compound 46 was synthesized in a similar way as described for Compound3. ¹H-NMR (CDCl₃) δ 3.75 (s, 6H), 3.85 (s, 3H), 4.28 9S, 4H), 6.80-7.30(m, 5H), 8.28 (s, 1H) ppm; ESMS calcd for C₂₀H₁₉NO₆: 369.1; found: 370.1(M+H⁺).

Compound 24-(Naphthalen-2-yl)-5-(2-hydroxy-4-methoxy-5-ethyl-phenyl)-isoxazole

To a mixture of 4-ethyl-benzene-1,3-diol (a, 10 mmol) andnaphthalen-2-yl-acetonitrile (b, 10 mmol) in boron trifluoride etherate(20 mL) was bubbled gaseous HCl for 12 h. The solids that formed werecollected by filtration and heated in 6N HCl (100 mL) and EtOH (20 mL)for 6 h. The mixture was diluted with water and extracted with CH₂Cl₂.The organic extract was washed with water and dried. The oil obtained onconcentration of the organic layer was crystallized in EtOAc/hexanes togive 1-(5-ethyl-2,4-dihydroxy-phenyl)-2-naphthalen-2-yl-ethanone (c,0.74 g).

To 1-(5-ethyl-2,4-dihydroxy-phenyl)-2-naphthalen-2-yl-ethanone (c, 0.50g) was added a mixture of pyridine (2 mL), trimethyl orthoformate (2 mL)and piperidine (2 drops), and the mixture was heated at 120° C. for 12h. The mixture was cooled to room temperature, diluted with EtOAc (100mL) then washed with 1 N HCl (100 mL). The organic layer was washed withwater and dried. The oil obtained on concentration of the organic layerwas crystallized in EtOAc/hexanes to give6-ethyl-7-hydroxy-3-naphthalen-2-yl-chromen-4-one (d, 0.36 g).

6-Ethyl-7-hydroxy-3-naphthalen-2-yl-chromen-4-one (d, 0.36 g) wasdissolved in dry dimethyl formamide (DMF) (5 mL) and treated withiodomethane (MeI) (0.5 mL) and potassium carbonate (1 g) at roomtemperature for 2 h. The mixture was diluted with water (50 mL) and theprecipitate was collected by filtration, washed with water and driedunder vacuum to give 6-ethyl-7-methoxy-3-naphthalen-2-yl-chromen-4-one(e, 0.36 g).

A mixture of 6-ethyl-7-methoxy-3-naphthalen-2-yl-chromen-4-one (e, 0.36g), hydroxylamine hydrochloride (0.6 g), triethylamine (0.5 mL) in EtOH(10 mL) was heated at 140° C. in microwave reactor for 4 h. The mixturewas diluted with water (100 mL) and extracted with CH₂Cl₂ (2×50 mL). Thecombined organic extracts were washed with water and dried using adrying agent. The oil obtained on concentration was flashchromatograghed on silica gel to give4-(naphthalen-2-yl)-5-(2-hydroxy-4-methoxy-5-ethyl-phenyl)-isoxazole aswhite powder (f, 0.19 g). ¹H-NMR (CDCl₃) δ (ppm) 8.57 (s, 1H), 7.8 (m,4H), 7.5 (m, 3H), 7.10 (s, 1H), 6.52 (s, 2H), 3.92 (s, 3H), 2.4 (q, 2H,J=7), 1.0 (t, 3H, J=7); ESMS clcd for C₂₂H₁₉NO₃: 345.1; Found: 346.0(M+H)⁺.

Compound 1634-(4-Chloro-phenyl)-5-(2-hydroxy-4-methoxy-5-ethyl-phenyl)-isoxazole

Compound 163 was synthesized in a similar manner as described forCompound 2. ¹H-NMR (CDCl₃) δ (ppm) 8.40 (s, 1H), 7.6 (d, 2H, J=8), 7.3(m, 2H), 7.02 (s, 2H), 6.52 (s, 1H), 3.86 (s, 3H), 2.4 (q, 2H, J=7), 1.0(t, 3H, J=7); ESMS clcd for C₁₈H₁₆ClNO₃: 329.1; Found: 330.0 (M+H)⁺.

Compound 1644-(4-Methyl-phenyl)-5-(2-hydroxy-4-methoxy-5-ethyl-phenyl)-isoxazole

Compound 164 was synthesized in a similar manner as described forCompound 2. ¹H-NMR (CDCl₃) δ (ppm) 8.40 (s, 1H), 7.3 (d, 2H, J=8), 7.2(d, 2H, J=8), 7.10 (s, 1H), 6.52 (s, 1H), 6.42 (s, 1H), 3.84 (s, 3H),2.4 (q, 2H, J=7), 2.18 (s, 3H), 1.0 (t, 3H, J=7); ESMS clcd forC₁₉H₁₉NO₃: 309.1; Found: 310.0 (M+H)⁺.

Compound 1654-(4-Amino-phenyl)-5-(2-hydroxy-4-methoxy-5-ethyl-phenyl)-isoxazole

Compound 165 was synthesized in a similar manner as described forCompound 2. ¹H-NMR (CDCl₃) δ (ppm) 8.28 (s, 1H), 7.2 (d, 2H, J=8), 7.0(m, 2H), 6.88 (s, 2H), 6.32 (s, 1H), 4.0 (br, 2H), 3.85 (s, 3H), 2.4 (q,2H, J=7), 1.0 (t, 3H, J=7); ESMS clcd for C₁₈H₁₈N₂O₃: 310.1; Found:311.0 (M+H)⁺.

Compound 1664-(4-Trifluoromethyl-phenyl)-5-(2-hydroxy-4-methoxy-5-ethyl-phenyl)-isoxazole

Compound 166 was synthesized in a similar manner as described forCompound 2.

¹H-NMR (CDCl₃) δ (ppm) 8.47 (s, 1H), 7.7 (d, 2H, J=8), 7.5 (d, 2H, J=8),6.98 (s, 1H), 6.53 (s, 1H), 6.38 (s, 1H), 3.86 (s, 3H), 2.5 (q, 2H,J=7), 1.0 (t, 3H, J=7); ESMS clcd for C₁₉H₁₆F₃NO₃: 363.1; Found: 364.0(M+H)⁺.

Compound 1674-(4-Methoxy-phenyl)-5-(2-hydroxy-4-methoxy-5-ethyl-phenyl)-isoxazole

Compound 167 was synthesized in a similar manner as described forCompound 2. ¹H-NMR (CDCl₃) δ (ppm) 8.39 (s, 1H), 7.3 (d, 2H, J=8), 7.09(s, 1H), 6.9 (d, 2H, J=8), 6.51 (s, 1H), 6.37 (s, 1H), 3.84 (s, 6H), 2.4(q, 2H, J=7), 1.0 (t, 3H, J=7); ESMS clcd for C₁₉H₁₉NO₄: 325.1; Found:326.0 (M+H)⁺.

Compound 44-(4-Iodo-phenyl)-5-(2-hydroxy-4-methoxy-5-ethyl-phenyl)-isoxazole

Compound 4 was synthesized in a similar manner as described for Compound2. ¹H-NMR (CDCl₃) δ (ppm) 8.42 (s, 1H), 7.6 (d, 2H, J=8), 7.3 (m, 2H),7.00 (s, 2H), 6.50 (s, 1H), 3.84 (s, 3H), 2.4 (q, 2H, J=7), 1.0 (t, 3H,J=7); ESMS clcd for C₁₈H₁₆INO₃: 421.0; Found: 421.9 (M+H)⁺.

Compound 1624-(3,4-Dimethyl-phenyl)-5-(2-hydroxy-4-methoxy-5-ethyl-phenyl)-isoxazole

Compound 162 was synthesized in a similar manner as described forCompound 2. ¹H-NMR (CDCl₃) δ (ppm) 8.41 (s, 1H), 7.1 (m, 4H), 6.51 (s,1H), 6.42 (s, 1H), 3.84 (s, 3H), 2.4 (q, 2H, J=7), 2.29 (s, 3H), 2.26(s, 3H), 1.0 (t, 3H, J=7); ESMS clcd for C₂₀H₂₁ NO₃: 323.1; Found: 324.0(M+H)⁺.

Compound 3b 4-(4-Methoxy-phenyl)-3-(3,4,5-trimethoxy-phenyl)-isoxazole(1) Synthesis of3-(4-Methoxy-phenyl)-1-(3,4,5-trimethoxy-phenyl)-propenone

To a stirred solution of p-anislaldehyde (1.36 g, 10 mmol) and1-(3,4,5-trimethoxy-phenyl)-ethanone (2.1 g, 10 mmol) in ethyl alcohol(EtOH) (10 mL) was added a 50% solution of NaOH in H₂O (1 mL). After thereaction had proceeded to completion, volatile components were removedunder reduced pressure and the residue was taken up with ethyl acetate(EtOAc) (50 mL). The EtOAc layer was washed with H₂O (2×30 mL) and thendried with Na₂SO₄. After removal of EtOAc, the product was precipitatedout from EtOH/H₂O, Solid material collected by filtration and was washedby H₂O (20 mL) and 95% ethyl alcohol (10 mL). The product,3-(4-Methoxy-phenyl)-1-(3,4,5-trimethoxy-phenyl)-propenone (2.8 g, 85%yield), was obtained as a yellow solid. ¹H-NMR δ 3.85 (s, 3H), 3.90 (s,3H), 3.95 (s, 6H), 6.95 (d, 2H, J=8), 7.28 (s, 2H), 7.39 (d, 1H, J=15),7.65 (d, 2H, J=8), 7.85 (d, 1H, J=15) ppm.

(2) Synthesis of[3-(4-Methoxy-phenyl)-oxiranyl]-(3,4,5-trimethoxy-phenyl)-methanone

To a stirred solution of3-(4-Methoxy-phenyl)-1-(3,4,5-trimethoxy-phenyl)-propenone (1.64 g, 5mmol) and 1N NaOH (2.52 mL) in 95% EtOH (22 mL) was added a coldsolution of 30% H₂O₂ (0.77 mL) at room temperature. After 72 h stirring,the precipitated material was collected by filtration and washed with95% EtOH to afford[3-(4-methoxy-phenyl)-oxiranyl]-(3,4,5-trimethoxy-phenyl)-methanone as awhite solid (1.38 g, yield 80%). ¹H-NMR (CDCl₃) δ 3.81 (s, 3H), 3.92 (s,6H), 3.95 (s, 3H), 4.05 (d, 1H, J=2), 4.20 (1H, J=2), 6.95 (d, 2H, J=7),7.25-7.35 (m, 4H) ppm.

(3) Synthesis of4-(4-Methoxy-phenyl)-3-(3,4,5-trimethoxy-phenyl)-isoxazole

To a stirred solution of[3-(4-methoxy-phenyl)-oxiranyl]-(3,4,5-trimethoxy-phenyl)-methanone (0.5g, 1.45 mmol) in dry ether (15 mL) was added BF₃.Et₂O (2.52 mL) slowly.After the addition, it was heated to reflux for 1 h. After the reactionmixture had cooled to room temperature, it was poured into ice-H₂O (100mL). The etheral layer was separated and the aqueous layer was extractedwith ether (10 mL×3). The combined ether layers were washed with H₂O (20mL×2) and concentrated to dryness. The residue was then transferred withEtOH (3 mL) to a flask suited for a microwave reactor, and hydroxylaminehydrochloride (0.32 g, 4.6 mmol) and pyridine (1 mL) were added. Themixture was heated and stirred in a microwave reactor at 130° C. for 30min. The reaction mixture was then cooled to room temperature and pouredinto ice-H₂O (20 mL). The solid material was collected and washed withH₂O. After preparative HPLC or repeated solvating gas chromatography(SGC) (hexane to 14% Hexane/EtOAc), the product4-(4-Methoxy-phenyl)-3-(3,4,5-trimethoxy-phenyl)-isoxazole was obtainedas a light yellow solid. ¹H-NMR (CDCl₃) δ 3.70 (s, 6H), 3.82 (s, 3H),3.85 (s, 3H), 6.85 (s, 2H), 6.94 (d, 2H, J=8), 7.33 (d, 2H, J=8), 8.30(s, 1H) ppm; ESMS calcd for C₁₉H₁₉NO₅: 341.0; found: 342.0 (M+H⁺).

Compound 2022-methoxy-5-(5-(3,4,5-trimethoxyphenyl)isoxazol-4-yl)phenylcarbamate-PEG

A solution of2-methoxy-5-(5-(3,4,5-trimethoxyphenyl)isoxazol-4-yl)anilinehydrochloride (300 mg, 0.76 mmol) and triethylamine (0.22 mL, 1.60 mmol)in dichloromethane (3 mL) was added slowly to a solution of triphosgene(77 mg, 0.26 mmol) in dichloromethane (5 mL) at 0° C. under nitrogenatmosphere. The reaction mixture was stirred for 30 min at roomtemperature, and then cooled to 0° C. before the addition of PEG (1.53g, 0.76 mmol) and triethylamine (0.12 mL, 0.77 mmol) in 2 ml ofdichloromethane. The resulting reaction mixture was stirred for 3 h. andwashed with NaHCO₃ solution. The aqueous layer was extracted withdichloromethane (2×), and the combined organic layers were washed withsaturated NaCl solution, dried over Na₂SO₄ and evaporated. The crudeproduct was purified by silica gel column chromatography (20% MeOH inEA) to give desired product2-methoxy-5-(5-(3,4,5-trimethoxyphenyl)isoxazol-4-yl)phenylcarbamate-PEG(130 mg). ¹H NMR (CDCl₃): δ (ppm) 8.31 (s, 1H); 8.22 (s, 1H); 7.40 (s,1H); 7.02 (d, J=9.0 Hz, 2H); 6.91 (s, 2H); 6.88 (d, J=9.0 Hz, 1H); 4.31(m, 2H); 3.86 (m, 9H); 3.72-3.37 (m, ˜178H).

Synthesis of Amino-Acid Derivatives

[Hydroxy-(3,4,5-trimethoxy-phenyl)-methyl]-phosphonic acid dimethylester (1)

A round-bottom flask equipped with thermometer, condenser and gas inletwas charged with methanol (150 mL) and sodium methoxide (1.074 g, 20mmol) and cooled to 0° C. under nitrogen protection. To a stirredsolution were added subsequently dimethyl phosphate (19.52 g, 0.177 mol)and 3,4,5-trimethoxybenzaldehyde (30 g, 0.153 mol). A resulted solutionwas heated at 50° C. for 1 hour, cooled down to r.t. and treated withtrifluoroacetic acid (4.6 ml). The mixture was concentrated underreduced pressure, the residue dissolved in EtOAc (300 mL), washed oncewith 18% brine, then once with saturated brine, dried over sodiumsulfate. The filtered solution was concentrated until precipitationstarted. To the resulted suspension 1:1 mixture of t-butylmethyl etherand heptane was added (50 mL). Solid was filtered out, washed with twoportions (20 mL) of the same solvent mixture and vacuum-dried to give41.2 g (88%) of 1, LC purity 99.4% (AUC), m.p. 103-104° C.

2-(4-Methoxy-3-nitro-phenyl)-1-(3,4,5-trimethoxy-phenyl)-ethanone (2)

A round-bottom flask equipped with thermometer, condenser and gas inletwas purged and maintained under nitrogen and charged withhydroxy-(3,4,5-trimethoxy-phenyl)-methyl]-phosphonic acid dimethyl ester(10 g, 32.6 mmol), 3,4-dihydro-2H-pyran (3.57 g, 42.4 mmol), toluene(100 mL) and p-toluenesolfonic acid hydrate (62.1 mg, 0.01 eq). Resultedsolution was stirred at 55° C. for 1.5 hours. TLC (EtOAc) showed fullconversion of starting material into a less polar compound. Reactionmixture was cooled to −10° C. and a solution of sodiumbis(trimethylsilyl)amide in THF (1 M, 33.3 mL) was added drop-wise,followed by a solution of 4-methoxy-3-nitrobenzaldehyde (5.91 g, 32.6mmol) in THF (20 mL). Reaction mixture was stirred at 0° C. for 1 hourbefore allowed to warm to room temperature. TLC (Hx:EtOAc, 2:1) showedformation of Z/E isomers of2-[2-(4-methoxy-3-nitro-phenyl)-1-(3,4,5-trimethoxy-phenyl)-vinyloxy]-tetrahydro-pyranand traces of starting materials remaining. Reaction was quenched withwater (140 mL), diluted with EtOAc (60 mL) and transferred intoseparatory funnel. Organic layer was separated, washed with water (2×50mL), brine, and concentrated. A residue was dissolved in methanol (100mL) with energetic mechanical stirring, and 1M aqueous solution of HCl(10 mL) was added. Precipitation of product started soon, and a resultedsuspension was stirred for 1 hour. Solid was filtered out, washed withmethanol (50 mL), then with water (3×30 mL) and dried on filter followedby vacuum-drying at 60° C. until constant weight. Crude deoxybenzoin 2,6.81 g (58%) showed LC purity of ≧97% and was used in the next stepwithout further purification.

3-Dimethylamino-2-(4-methoxy-3-nitro-phenyl)-1-(3,4,5-trimethoxy-phenyl)-propenone(3)

200 mL round-bottom flask was charged with2-(4-methoxy-3-nitro-phenyl)-1-(3,4,5-trimethoxy-phenyl)-ethanone (6.81g, 18.8 mmol) and N,N-dimethylformamide dimethyl acetal (52 mL) andheated to 75° C. After all substrate dissolved, heating continued for 15min, and TLC indicated completion of reaction. Excess of DMF-DMA wasremoved under reduced pressure to give crude enamine 3 as an oilyresidue still containing some of the reagent (caution! product foams andclogs adaptors). It was used in the next step without purification.

4-(4-Methoxy-3-nitro-phenyl)-5-(3,4,5-trimethoxy-phenyl)-isoxazole (4)

Method A.

A flask containing crude enamine 3 (˜18.8 mmol) was charged withhydroxylamine hydrochloride 1.44 g, 20.7 mmol), sodium acetate (1.93 g,23.6 mmol), ethanol (58 mL) and water (29 mL). A resulted clear solutionwas acidified with acetic acid to pH 4-5 (˜11.2 mL) and refluxed for 4hours. Reaction was monitored by TLC (Hexane/EtOAc, 1:1) for theconversion of open-chain intermediate into less polar isoxazolederivative. Ice-water (59 mL) was added to the cooled reaction mixture,and stirring was continued for 1 hour to complete precipitation. A solidwas filtered out, washed with water (2×20 mL), with ethanol (15 mL) anddried to give crude isoxazole, 5.24 g (72%). Re-crystallization fromEtOAc/2-ProOH afforded 4.95 g (68%) of 4, purity>99.2% (AUC).

Method B.

A flask containing crude enamine 3 (˜10 mmol) was charged with methanol(23 mL), hydroxylamine hydrochloride (1.39 g, 20 mmol) and triethylamine(2.02 g, 20 mmol) and refluxed for one hour. TLC showed traces ofstarting material remained. Reaction mixture was concentrated usingvacuum pump to remove triethylamine. The residue was triturated withwater, water decanted from an oil, and that operation was repeated twomore times. The oil was then dissolved in ethanol with heating, ethanolwas partly removed from the solution and a solid precipitated. Crudeproduct was isolated by filtration and re-crystallized fromEtOAc/2-propanol to give 4, 2.67 g (69%).

Compound 642-Methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl]-phenylaminehydrochloride (5)

A 200-mL round-bottom flask equipped with T-bore stopcock connected to aballoon with hydrogen was charged with 4 (4.44 g, 11.5 mmol) and THF (40mL), and a mixture was stirred to dissolve a substrate. Methanol (22mL), solution of HCl in methanol (1M, 22 mL) and palladium, 10 wt % onactivated carbon (532 mg, 12 wt %) were added to the flask, the systemwas evacuated and stirred under atmosphere of hydrogen for 2 hours. TLCindicated completion of reaction (Hexane/EtOAc, 2:1, developed twotimes). Catalyst was filtered out and washed with methanol (15 mL×3).Filtrate was diluted with 2-propanol (20 mL) and concentrated underreduced pressure to ˜20 mL volume. A resulted suspension was dilutedwith EtOAc (20 mL), a solid was filtered out, washed with EtOAc (20×2)and dried to give crude amine hydrochloride 5 as a yellow solid, 3.3 g(80%), LC purity 97.1%. The solid was refluxed in ethanol (50 mL) for 15min to dissolve colored impurities. A cooled suspension was filteredout, washed with EtOAc (20×2) and vacuum-dried to obtain acreamy-colored solid, 2.9 g (70%), LC purity 99.1%.

({2-Methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl]-phenylcarbamoyl}-methyl)-carbamicacid tert-butyl ester (6)

To a solution of N-t-Boc-glycine (357 mg, 2 mmol) and N-methyl-imidazole(0.162 mL, 2 mmol) in THF (16 mL) cooled with ice methanesulfonylchloride (0.158 mL, 2 mmol) was added. Ice batch was removed, compound 5(0.4 g, 1 mmol) was added as a solid, followed by thriethylamine (0.144mL, 2.02 mmol), and the reaction mixture was stirred at 40-50° C.overnight. A resulted solution was decanted from a solid, a flask rinsedwith EtOAc, and a combined organic solution was washed with saturatedammonium chloride solution, then twice with water, brine and dried overanhydrous sodium sulfate. The solution was filtered out through a celitepad, concentrated and the residue was dissolved in 2-propanol (3 mL)with heating, and hexane (1-2 mL) was added drop-wise to startprecipitation. In 1 hour a solid was filtered out, washed with 1:1Hexane:ether mixture (10 ml×2) and vacuum-dried to give compound 6, 0.49g (93.7%), LC purity 99%. ¹H NMR (DMSO-d₆): δ 9.11 (s, 1H), 8.81 (s,1H), 8.22 (s, 1H), 7.24 (m, 1H), 7.20-7.15 (m, 2H), 6.91 (s, 2H), 3.87(s, 3H), 3.73 (m, 2H), 3.70 (s, 3H), 3.66 (s, 6H). 1.40 (s, 9H).

Compound 1692-Amino-N-{2-methoxy-5-[5-(3,4,5-trimethoxy-phenyl)-isoxazol-4-yl]-phenyl}-acetamide(7)

To a solution of 6 in THF (6 mL) a 1M solution of HCl in ethanol (17 mL)was added, and a resulted solution was stirred overnight at roomtemperature to form a suspension with product partly precipitated out.The reaction mixture was concentrated under reduced pressure keepingtemperature below 45° C. to ˜10 mL volume. A solid was filtered out,washed with ether (5 ml×2), hexane (5 mL) and vacuum-dried to give atitle compound 7, 353 mg (84%), LC purity 99%.

¹H NMR (DMSO-d₆): δ 9.86 (s, 1H), 8.80 (s, 1H), 8.12 (brs, 3H), 8.07 (d,J=1.8 Hz, 1H), 7.25 (td, J=8.4 and 1.8 Hz, 1H), 7.20 (d, J=8.9 Hz, 1H),6.90 (s, 2H), 3.89 (s, 3H), 3.83 (m, 2H), 3.70 (s, 3H), 3.67 (s, 6H).

Compound 1732-amino-N-(2-methoxy-5-(5-(3,4,5-trimethoxyphenyl)isoxazol-4-yl)phenyl)butanamidehydrochloride

Compound 173 was synthesized in a similar manner as described forCompound 169. ¹H NMR (CDCl₃): δ (ppm) 8.78-8.22 (m, 5H); 7.15 (s, 1H);6.84-6.72 (m, 3H); 3.84-3.70 (m, 12H); 3.48 (m, 2H); 1.23 (m, 3H); 0.98(m, 2H). ESMS calcd (C₂₃H₂₈ClN₃O₆): 477.17; found: 477.2 (M+H)⁺

Compound 1742-amino-N-(2-methoxy-5-(5-(3,4,5-trimethoxyphenyl)isoxazol-4-yl)phenyl)-3-phenylpropanamidehydrochloride

Compound 174 was synthesized in a similar manner as described forCompound 169. ¹H NMR (CDCl₃): δ (ppm) 8.82 (s, 1H); 8.22 (m, 2H);7.15-6.66 (m, 8H); 3.82-3.58 (m, 14H). ESMS calcd (C₂₈H₃₀ClN₃O₆):539.18; found: 539.2 (M+H)⁺

Compound 1722-amino-N-(2-methoxy-5-(5-(3,4,5-trimethoxyphenyl)isoxazol-4-yl)phenyl)-4-(methylthio)butanamidehydrochloride

Compound 172 was synthesized in a similar manner as described forCompound 169. ¹H NMR (CDCl₃): δ (ppm) 8.79 (m, 2H); 8.36 (m, 1H); 7.08(m, 1H); 6.84 (m, 2H); 3.86-3.72 (m, 9H); 2.75-2.15 (m, 4H); 2.07 (m,3H), ESMS calcd (C₂₄H₃₀ClN₃O₆S): 523.15; found: 523.1 (M+H)⁺

Compound 1762-amino-N-(2-methoxy-5-(5-(3,4,5-trimethoxyphenyl)isoxazol-4-yl)phenyl)-3-(4-methoxyphenyl)propanamide

Compound 176 was synthesized in a similar manner as described forCompound 169. ¹H NMR (CDCl₃): δ (ppm) 8.90-8.78 (m, 2H); 8.27 (m, 2H),7.23-6.68 (m, 5H); 3.83-3.68 (m, 12H); 2.10 (m, 2H). ESMS calcd(C₂₉H₃₂ClN₃O₇): 569.19; found: 569.1 (M+H)⁺

Compound 1752-amino-N-(2-methoxy-5-(5-(3,4,5-trimethoxyphenyl)isoxazol-4-yl)phenyl)-4-methylpentanamidehydrochloride

Compound 175 was synthesized in a similar manner as described forCompound 169. ¹H NMR (D₂O): δ (ppm) 8.15 (s, 1H); 7.37 (s, 1H); 6.78 (m.2H); 6.31 (m, 2H); 4.02 (m, 1H); 3.62 (m, 8H); 3.31 (m, 8H); 1.56 (m,3H); 0.71 (m, 6H). ESMS calcd (C₂₅H₃₂ClN₃O₆): 505.20; found: 505.2(M+H)⁺

Compound 241 methyl2-(2-(2-methoxy-5-(5-(3,4,5-trimethoxyphenyl)isoxazol-4-yl)phenylamino)-2-oxoethylamino)acetate

Compound 274 was synthesized in a similar manner as described forCompound 169. ¹H NMR (CDCl₃): δ (ppm) 9.88 (s, 1H), 9.24 (s, 1H), 8.30(m, 2H), 7.94 (m, 1H), 7.56 (m, 1H), 7.03-6.77 (m, 4H), 4.42-3.44 (m,18H). ESMS calcd (C₂₄H₂₈ClN₃O₈): 521.16; found: 521.1 (M+H)⁺

Compound 2424-amino-5-(2-methoxy-5-(5-(3,4,5-trimethoxyphenyl)isoxazol-4-yl)phenylamino)-5-oxopentanoic acid hydrochloride

Compound 275 was synthesized in a similar manner as described forCompound 169. ¹H NMR (CDCl₃): δ (ppm) 9.38 (s, 1H); 8.34-8.04 (m, 3H);6.82-6.66 (m, 4H); 3.62 (m, 16H); 2.7-2.4 (m, 4H). ESMS calcd(C₂₄H₂₅ClN₃O₆): 521.16; found: 521.1 (M+H)+

Compound 2433-amino-N-(2-methoxy-5-(5-(3,4,5-trimethoxyphenyl)isoxazol-4-yl)phenyl)propanamide hydrochloride

Compound 276 was synthesized in a similar manner as described forCompound 169. ¹H NMR (D₂O): δ (ppm) 8.23 (s, 1H); 7.47 (m, 1H); 6.82 (m,2H); 6.45 (m, 2H); 3.68 (m, 4H); 3.56 (m, 6H); 3.39 (m, 6H); 2.65 (m,4H). ESMS calcd (C₂₂H₂₆ClN₃O₆): 463.15; found: 463.1 (M+H)⁺

Compound 2443-amino-N-(2-methoxy-5-(5-(3,4,5-trimethoxyphenyl)isoxazol-4-yl)phenyl)-4-methylpentanamidehydrochloride

Compound 277 was synthesized in a similar manner as described forCompound 169. ¹H NMR (D₂O): δ (ppm) 8.27 (s, 1H); 7.44 (m, 1H); 6.89 (m,2H); 6.52 (m, 2H); 3.69 (m, 5H); 3.56 (m, 4H); 3.42 (m, 7H); 3.31 (m,3H); 2.65 (m, 4H); 1.78 (m, 2H). ESMS calcd (C₂₅H₃₂ClN₃O₆): 505.20;found: 505.2 (M+H)⁺

Compound 2042-amino-N-(2-methoxy-5-(5-(3,4,5-trimethoxyphenyl)isoxazol-4-yl)phenyl)propanamide hydrochloride

Compound 219 was synthesized in a similar manner as described forCompound 169. ¹H NMR (CDCl₃): δ (ppm) 8.32 (s, 1H); 8.22 (s, 1H). 7.16(m, 2H), 6.90 (m, 3H); 3.90-3.70 (m, 15H); 1.90 (m, 4H). ESMS calcd(C₂₂H₂₆ClN₃O₆): 463.15; found: 463.1 (M+H)⁺

Compound 2492-methoxy-5-(5-(3,4,5-trimethoxyphenyl)isoxazol-4-yl)aniline

¹H NMR (DMSO-d₆): δ 8.72 (s, 1H), 6.95 (s, 2H), 6.86 (d, J=7.8 Hz, 1H),6.75 (d, J=1.8 Hz, 1H), 6.64-6.61 (m, 1H), 4.87 (s, 2H), 3.78 (s, 3H),3.70-3.68 (m, 9H).

Example 2 Cytotoxicity of Compounds of the Invention

Tumor cell line, MDA-435, was seeded in 96-well plates at 1×10⁴cells/well in DMEM medium and treated with compounds at differentconcentrations. Taxol was used as a positive control. The cells wereincubated at 37° C. for 70 h. Viability of the cells was measured withCell Counting Kit 8 (Dojindo, Cat # CK04). IC₅₀ of the compounds wasdetermined by Five-Parameter Logistic equation. As can be seen fromTable 2 several compounds of the invention have IC₅₀ values comparableto Taxol.

TABLE 2 compound IC₅₀ (nM) Taxol 16 1 132 2 79 3 16 4 232 6 461 44 20045 219 46 21 47 47 161 591 162 842 168 >1000

Example 3 Cytotoxicity of Compounds of the Invention in MultidrugResistant Cell Lines

The in vitro cytotoxicity of the compounds of the invention wasdetermined in the following human cell lines: HL-60 (T-cell leukemia),MDA-435 and MCF-7 (human breast carcinoma), NC1-H460 and H29 (coloncarcinoma), DU145 (prostate carcinoma), and MES-SA and MES-SA/DX5(uterine sarcoma). MES-SA is a model of uterine sarcoma, and the cellare sensitive to a number of chemotherapeutic agents includingdoxorubicin, dactinomycin, mitomycin C, taxol and bleomycin, butresistant to vinblastine and cisplatin. MES-SA/Dx5 was established inthe presence of increasing concentrations of doxorubicin. The cellsexpress high levels of mdr-1 mRNA and p-glycoprotein and exhibit crossresistance to more than fifteen chemotherapeutic agents including taxol,etoposide, mitomycin C, colchicine, vinblastine, dactinomycin,5-fluorouracil, methotrexate and so on. All cells were purchased fromATCC.

The cell lines were maintained in RPMI1640 (GIBCO) supplemented with 10%FCS, 100 units/mL penicillin, 100 ug/ml streptomycin, and 2 mML-glutamine. Cells were split every third day and diluted to aconcentration of 2×105 cells/mL one day before the experiment wasperformed. All experiments were performed on exponentially growing cellcultures. Cell densities were 2.5×10⁴ cells/mL in all experiments.

Compounds of the invention were prepared by dissolving the compound at aconcentration of 10 mM in 100% DMSO. Final concentrations 10, 1, 0.1,0.01 and 0.001 μM were obtained by diluting the stock solution directlyinto the tissue culture medium. Cells were incubated with varyingconcentrations of compounds for 72 hours and the IC₅₀ was determined byMTS (i.e. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide)assay. IC₅₀ in this context stands for the concentration of compoundrequired to inhibit 50% tumor cell growth. As can be seen from Tables 3and 4, compounds of the invention showed much greater activity thanTaxol against multidrug resistant cell line MES/DX5.

TABLE 3 Comp. 3 Comp. 46 Comp. 4 Taxol Cell IC₅₀ IC₅₀ IC₅₀ IC₅₀ LineCell Type in μM in μM in μM in μM HL60 Leukemia 0.005 0.05 0.05 0.005MDA-435 Breast Cancer 0.005 0.05 0.05 0.002 MCF-7 Breast Cancer 0.010.05 0.05 0.005 NCI-H460 Colon 0.005 0.05 0.05 0.005 Carcinoma MES-SAUterine 0.01 0.05 0.05 0.005 Carcinoma MES/DX5 MDR-1 0.005 0.05 0.05 10DU145 Prostate 0.005 0.1 0.05 0.005 Carcinoma H29 Colon 0.005 0.05 0.050.01 Carcinoma

TABLE 4 Cell Line: HL60 MES-SA MES/DX5 Cell Type: Compound LeukemiaUterine Carcinoma MDR-1 No. IC₅₀ in μM IC₅₀ in μM IC₅₀ in μM 169 0.0070.003 0.003 170 0.002 0.009 0.003 171 0.005 0.002 0.004 172 0.005 0.00010.0001 173 0.002 0.0001 0.0001 174 0.002 0.0001 0.0001 175 0.005 0.00010.0001 176 0.064 0.0001 0.0001 177 0.052 0.008 0.004 178 0.022 0.0040.004 202 >1.0 >1.0 >1.0 204 0.500 0.106 0.120 241 0.600 0.136 0.063 2430.063 0.050 0.038 249 0.001 0.001 0.001

Example 4 Induction of Apoptosis by Compounds of the Invention

SB cells (2×10⁵ cells/mL) were cultured in 12-well plates (2 mL/well)and were left untreated (negative control), treated with Taxol (positivecontrol), or treated with a compound of the invention for 24 h at 37° C.After treatment, the cells were washed one time with 1×PBS and stainedwith FITC labeled anti-Annexin V and PI (10 pg/ml) for 15 min at roomtemperature. The cells were analyzed by FACSCalibur (Becton Dickinson).As can be seen from Table 5, many compounds of the invention were morepotent apoptosis inducers in SB cells than Taxol.

TABLE 5 Compound # % Live % Apoptotic % Dead (1 μM) Cells Gated CellsGated Cells Gated Untreated Cells 68.75 10.85 11.88 Taxol 63.74 17.8412.50 1 60.15 18.36 14.41 2 45.72 22.73 22.67 3 46.43 22.99 21.79 452.82 19.05 20.15 6 59.17 14.17 17.31 44 64.77 16.05 12.27 45 62.0517.74 15.37 46 51.04 19.04 17.33 47 61.85 13.83 14.76 161 66.80 14.6110.49 162 64.62 17.74 11.52 168 60.37 15.49 14.38

Example 5 Hepatocyte Toxicity

Hepatocytes isolated from normal rats were seeded in 96-well platescoated with extracellular matrix at 1.5×10⁴ cells/well. The cells wereuntreated (negative control), treated with 17AAG (positive control) orTaxol (positive control), or treated with a compound of the invention atdifferent concentrations at 37° C. for 48 h. Viability of the cells wasmeasured with Cell Counting Kit 8. FIGS. 1 and 2 show that the compoundsof the invention had similar cytotoxic effects on normal hepatocytescompared to Taxol and had less cytotoxic activity than 17AAG at 1 to 20uM.

Example 6 Cell Cycle Analysis

MDA-435 cells were cultured in 6-well plates at 1×10⁶ cells/well andwere untreated (negative control), treated with Taxol (positivecontrol), or treated with a compound of the invention at 37° C. for 20h. The cells were detached with 1× trypsin and washed one time with PBS.Cycle TEST PLUS kit (BD PharMingen, Cat #340242) was used to stain thecells. Cell cycle was analyzed with FACScomp program (BS PharMingen). Ascan be seen from Table 6, compounds of the invention decrease thepercentage of cells entering mitosis (G2/M phase) and increase theapoptotic population compared to untreated cells.

TABLE 6 G0/G1 S G2/M Apoptotic Phase Phase Phase Population Treatment(%) (%) (%) (%) Untreated 34.60 26.58 36.09 3.26 Taxol (30 nM) 19.1232.93 32.32 16.17 Comp. 1 (100 nM) 19.15 37.60 32.60 11.35 Comp. 2 (500nM) 21.25 37.67 30.53 11.17 Comp. 3 (10 nM) 17.72 37.96 29.92 14.99Comp. 6 (800 mM) 18.45 35.55 35.96 10.59 Comp. 46 (50 nM) 19.67 37.9828.18 9.88

Example 7 Inhibition of Tubulin Polymerization by Compounds of theInvention

Material and Methods:

Wild-type Chinese Hamster Ovary cells (WT CHO) cells were maintained inHam's F-12 medium supplemented with 10% fetal bovine serum (FBS;HyClone, Logan, Utah). Cells of low density (˜20%) growing on 2-wellchambered cover-slips (Labtek (Campbell, Calif.) or Fisher Scientific)were transfected with a mammalian expression vector encodingα-tubulin-YFP (Clontech, Palo Alto, Calif.) with the use of FuGENE 6(Roche Molecular Biochemicals, Indianapolis, Ind.), according to themanufacturer's instructions. Twenty-four hours after transfection, thecells were cultured in 400 pg/ml G418 (Invitrogen, Carlsbad,Calif.)-containing selection medium for 2 weeks. Living cells wereexamined using a fluorescent microscope for α-tubulin-YFP expression.Cells in single colonies containing microtubules labeled withα-tubulin-YFP were lifted and expanded in G418-containing medium.Expression of α-tubulin-YFP was confirmed by the presence of thetubulin-YFP labeled microtubule pattern identical to immunostainedmicrotubule pattern of non-transfected cells, as well as by subjectingthe cells to Western blot analysis using an anti-GFP antibody (RocheMolecular Biochemicals, Basel, Switzerland) and confirming the correctmass of the α-tubulin-YFP chimeric protein. Expressed tubulin-YFP wasdetected as a single band in Western blots. The tubulin-YFP expressingcell lines (referred as CHO-α-tubulin-YFP cells) were used in thestudies described below. Similar methods were used to generate MCF-7cell lines stably expressing α-tubulin-YFP (referred asMCF₇-α-tubulin-YFP cells).

CHO-α-tubulin-YFP or MCF7-α-tubulin-YFP cells were cultured in 2-wellchambered cover-slips (Labtek (Campbell, Calif.) or Fisher Scientific)for 24 hours before treatment with a compound of the invention. Forcomparison of the effects of treatment on α-tubulin-YFP labeledmicrotubules with the compounds of the invention, CHO-α-tubulin-YFP orMCF7-α-tubulin-YFP cells were treated with the a compound of theinvention, Taxol or equivalent concentrations of DMSO-containing mediafor various time periods before imaging. Tubulin-YFP fluorescence inliving cells or fixed cells was captured using a standard filter forFITC and objectives of 20× or 60× magnification on a Nikon TE300microscope with a Leica DC50 color digital camera (Leica, Bannockburn,Ill.) or a CoolSnap HQ monochrome CCD camera (Photonetrics, Tucson,Ariz.). The Leica DC50 and CoolSnapHQ cameras were controlled with LeicaDC50 software and MetaVue/MetaMorph software, respectively (UniversalImaging Corp, Downingtown, Pa.). Tubulin-YFP signal in live cells ispresent as typical microtubule network (normal condition, see FIG. 3which shows DMSO treated MCF7-α-tubulin-YFP cells), microtubule bundleformation (stabilized microtubules, see FIG. 4 which showsMCF7-α-tubulin-YFP cells treated with 0.1 μM Taxol), or cytoplasmicpattern (depolymerized tubulin-YFP, see FIGS. 5, 6 and 7 which showMCF₇-α-tubulin-YFP cells treated with 1.0 μM Compounds 1, 3, and 6 ofthe invention, respectively). As can be seen from the Figures, thecompounds of the invention inhibit tubulin polymerization.

Example 8 Compounds of the Invention Disrupt Microtubules in CellsResistant to the Depolymerization Effects of Colchicine and Vincristine

The effects of compounds of the invention on microtubules were studiedin CV-1 cells. The microtubules of CV-1 cells are known to be resistantto the depolymerizing effects of colchicine and vincristine. CV-1 cellswere treated with 500 nM of either Compound 3, vincristine, orcolchicines, and their microtubules were examined at 24, 48 and 72 hr(FIGS. 8, 9 and 10). Cells were then fixed and stained to examinemicrotubule structure. In cells treated with Compound 3 for 24 hrs, nomicrotubule structure was found (FIGS. 8B and 8E). However, disorganizedbut clear microtubule structures were found in cells treated with eithervincristine (FIG. 8D) or colchicines (FIG. 8C). At 48 hr treatment,cells with Compound 3 still contained no microtubule structures (FIGS.9B and 9E), while microtubule structures were still found in vincristine(FIG. 9D), colchicines (FIG. 9C) and DMSO (FIG. 9A) treated cells. Mostinterestingly, at 72 hr of treatment with Compound 3 (FIGS. 10B and10E), most cells contained fragmented, short, and strongly stainedtubular structures in the cytoplasm. These data suggest that Compound 3is a more potent disrupter of microtubule function that eithervincristine or colchicine.

Example 9 Compound 3 Displays Anti-Tumor Activity Against Human TumorCells Line in Nude Mouse Xenograft Models

The human tumor cell line, MDA-MB-435S (ATCC #HTB-129; G. Ellison, etal., Mol. Pathol. 55:294-299, 2002), was obtained from the American TypeCulture Collection (ATCC; Manassas, Va., USA). The human tumor cellline, RERF-LC-Al (RCB0444; S. Kyoizumi, et al., Cancer. Res.45:3274-3281, 1985), was obtained from the Riken Cell Bank (RCB;Tsukuba, Ibaraki, Japan). The cell lines were cultured in growth mediaprepared from 50% Dulbecco's Modified Eagle Medium (high glucose), 50%RPM! Media 1640, 10% fetal bovine serum (FBS), 1% 100×L-glutamine, 1%100× Penicillin-Streptomycin, 1% 100× sodium pyruvate and 1% 100×MEMnon-essential amino acids. FBS was obtained from ATCC and all otherreagents were obtained from Invitrogen Corp. (Carlsbad, Calif., USA).Approximately 4-5×10(6) cells that had been cryopreserved in liquidnitrogen were rapidly thawed at 37° C. and transferred to a 175 cm²tissue culture flask containing 50 ml of growth media and then incubatedat 37° C. in a 5% CO₂ incubator. The growth media was replaced every 2-3days until the flask became 90% confluent, typically in 5-7 days. Topassage and expand the cell line, a 90% confluent flask was washed with10 mL of room temperature phosphate buffered saline (PBS) and the cellswere disassociated by adding 5 mL 1× Trypsin-EDTA (Invitrogen) andincubating at 37° C. until the cells detached from the surface of theflask. To inactivate the trypsin, 5 mL of growth media was added andthen the contents of the flask were centrifuged to pellet the cells. Thesupernatant was aspirated and the cell pellet was resuspended in 10 mLof growth media and the cell number determined using a hemocytometer.Approximately 1−3×10(6) cells per flask were seeded into 175 cm² flaskscontaining 50 mL of growth media and incubated at 37° C. in a 5% CO₂incubator. When the flasks reached 90% confluence, the above passagingprocess was repeated until sufficient cells had been obtained forimplantation into mice.

Seven to eight week old, female Crl:CD-1-nuBR (nude) mice were obtainedfrom Charles River Laboratories (Wilmington, Mass., USA). Animals werehoused 4-5/cage in micro-isolators, with a 12 hr/12 hr light/dark cycle,acclimated for at least 1 week prior to use and fed normal laboratorychow ad libitum. Studies were conducted on animals between 7 and 19weeks of age at implantation. To implant MDA-MB-4355 tumor cells intonude mice, the cells were trypsinized as above, washed in PBS andresusupended at a concentration of 50×10(6) cells/mL in PBS. Using a 27gauge needle and 1 cc syringe, 0.1 mL of the cell suspension wasinjected into the corpus adiposum of nude mice. The corpus adiposum is afat body located in the ventral abdominal vicera in the right quadrantof the abdomen at the juncture of the os coxae (pelvic bone) and the osfemoris (femur). To implant RERF-LC-Al tumor cells into nude mice, thecells were trypsinized as above, washed in PBS and resuspended at aconcentration of 50×10(6) cells/mL in 50% non-supplemented RPMI Media1640 and 50% Matrigel Basement Membrane Matrix (#354234; BD Biosciences;Bedford, Mass., USA). Using a 27 gauge needle and 1 cc syringe, 0.1 mLof the cell suspension was injected subcutaneously into the flank ofnude mice.

Tumors were then permitted to develop in vivo until they reachedapproximately 100-200 mm³ in volume, which typically required 2-3 weeksfollowing implantation. Tumor volumes (V) were calculated by calipermeasurement of the width (W), length (L) and thickness (T) of tumorsusing the following formula: V=0.5326×(L×W×T). Animals were randomizedinto treatment groups so that the average tumor volumes of each groupwere similar at the start of dosing.

Stock solutions of test articles were prepared by dissolving theappropriate amounts of each compound in dimethyl sulf oxide (DMSO) bysonication in an ultrasonic water bath. Stock solutions were prepared atthe start of the study, stored at −20° C. and diluted fresh each day fordosing. A solution of 20% Cremophore RH40 (polyoxyl 40 hydrogenatedcastor oil; BASF Corp., Aktiengesellschaft, Ludwigshafen, Germany) in80% D5W (5% dextrose in water; Abbott Laboratories, North Chicago, Ill.,USA) was also prepared by first heating 100% Cremophore RH40 at 50-60°C. until liquefied and clear, diluting 1:5 with 100% D5W, reheatingagain until clear and then mixing well. This solution was stored at roomtemperature for up to 3 months prior to use. To prepare formulations fordaily dosing, DMSO stock solutions were diluted 1:10 with 20% CremophoreRH40. The final formulation for dosing contained 10% DMSO, 18%Cremophore RH40, 3.6% dextrose, 68.4% water and the appropriate amountof test article (Compound 3 or paclitaxel). Animals were intravenously(i.v.) injected with this solution at 10 ml per kg body weight on aschedule of 3 days per week (Monday, Wednesday, Friday, with no dosingon Saturday and Sunday) for a total of 9-10 doses.

As shown in FIG. 11, treatment with 6.25, 12.5 and 25 mg/kg body weightof Compound 3 decreased the growth rate of MDA-MB-435S melanoma cells innude mice. Tumor regression was observed at the two highest dose levelsof Compound 3. Treatment with 6.25 mg/kg of Compound 3 or with 7.5 mg/kgof paclitaxel (an unrelated drug that is used to treat cancer in humans)resulted in decreased tumor growth compared to animals treated withvehicle alone. This effect was not associated with overt toxicity ofCompound 3, as shown by the minimal effect on body weights (FIG. 12).

As shown in FIG. 13, treatment with 25 mg/kg body weight of Compound 3also decreased the growth rate of RERF-LC-Al lung tumor cells in nudemice. This effect was not associated with overt toxicity, as shown bythe minimal effect on body weights (FIG. 14).

Example 10 Compounds 169, 174, and 178 Display Anti-Tumor ActivityAgainst Human Tumor Cells Line in a nude Mouse Xenograft Model

The human tumor cell line, MDA-MB-435S (ATCC #HTB-129; G. Ellison, etal., Mol. Pathol. 55:294-299, 2002), was obtained and cultured asdescribed in Example 9 above. Seven to eight week old, femaleCrl:CD-1-nuBR (nude) mice were obtained from Charles River Laboratories(Wilmington, Mass., USA). Animals were housed 4-5/cage inmicro-isolators, with a 12 hr/12 hr light/dark cycle, acclimated for atleast 1 week prior to use and fed normal laboratory chow ad libitum.Studies were conducted on animals between 8 and 10 weeks of age atimplantation. To implant MDA-MB-4355 tumor cells into nude mice, thecells were trypsinized as above, washed in PBS and resusupended at aconcentration of 50×10(6) cells/ml in PBS. Using a 27 gauge needle and 1cc syringe, 0.1 ml of the cell suspension was injected into the corpusadiposum of nude mice. The corpus adiposum is a fat body located in theventral abdominal vicera in the right quadrant of the abdomen at thejuncture of the os coxae (pelvic bone) and the os femoris (femur).

Tumors were then permitted to develop in vivo until the majority reachedan average of 100-200 mm³ in tumor volume, which typically required 2-3weeks following implantation. Animals with oblong, very small or largetumors were discarded, and only animals carrying tumors that displayedconsistent growth rates were selected for studies. Tumor volumes (V)were calculated by caliper measurement of the width (W), length (L) andthickness (T) of tumors using the following formula: V=0.5236×(L×W×T).Animals were randomized into treatment groups so that the median tumorvolumes of each group were similar at the start of dosing. % T/C values,as a measure of efficacy, were determined as follows:

-   -   (i) If ΔT>0: %°T/C=(ΔT/□C)×100    -   (ii) If ΔT<0: % T/C=(ΔT/T₀)×100    -   (iii) ΔT=Change in median tumor volume between start of dosing        and the end of study.    -   (iv) ΔC=Change in median tumor volume between start of dosing        and the end of study.    -   (v) T₀=Median tumor volume at start of dosing.

Compounds were formulated in either D5W (Compounds 169 and 174) or DRD(Compound 178). For formulations in D5W, solutions of test articles wereprepared by dissolving the appropriate amounts of each compound in 5%dextrose in water (Abbott Laboratories, North Chicago, Ill., USA) bysonication in an ultrasonic water bath. For formulations in DRD, stocksolutions of test articles were prepared by dissolving the appropriateamounts of each compound in dimethyl sulfoxide (DMSO) by sonication inan ultrasonic water bath. Stock solutions were prepared weekly, storedat −20° C. and diluted fresh each day for dosing. A solution of 20%Cremophore RH40 (polyoxyl 40 hydrogenated castor oil; BASF Corp.,Aktiengesellschaft, Ludwigshafen, Germany) in 5% dextrose in water(Abbott Laboratories, North Chicago, Ill., USA) was also prepared byfirst heating 100% Cremophore RH40 at 50-60° C. until liquefied andclear, diluting 1:5 with 100% D5W, reheating again until clear and thenmixing well. This solution was stored at room temperature for up to 3months prior to use. To prepare DRD formulations for daily dosing, DMSOstock solutions were diluted 1:10 with 20% Cremophore RH40. The finalDRD formulation for dosing contained 10% DMSO, 18% Cremophore RH40, 3.6%dextrose, 68.4% water and the appropriate amount of test article.Animals were intravenously (i.v.) injected with these formulations at 10ml per kg body weight on schedules of either 1 day per week for a totalof 3 doses, or 3 days per week (Monday, Wednesday, Friday, with nodosing on Saturday and Sunday) for a total of 9 doses.

As shown in FIG. 15, treatment 1 time/week with doses of 2 mg/kg bodyweight of Compound 169 and 4.55 mg/kg body weight of Compound 174substantially decreased the growth rate of MDA-MB-435S cells in nudemice, with % T/C values of 38 and 25, respectively. This effect was notassociated with overt toxicity, as shown by the minimal effect on bodyweights (FIG. 16).

As shown in FIG. 17, treatment with Compound 178 3 times per week for atotal of 3 doses at 25 mg/kg body weight, followed by 3 times per weekfor a total of 3 doses at 37.5 mg/kg body weight, followed by 3 timesper week for a total of 3 doses at 50 mg/kg body weight (arrows) beganto show modest efficacy after the dose escalation reached 37.5 mg/kg.This effect was not associated with overt toxicity, as shown by theminimal effect on body weights (FIG. 18).

Example 11 Compound 3 Rapidly Induces Necrosis in a nude Mouse TumorModel

The mouse mammary carcinoma cell line, EMT6 (ATCC #CRL-2755), wasobtained from the American Type Culture Collection (ATCC; Manassas, Va.,USA). The cell line was cultured in growth media prepared from 50%Dulbecco's Modified Eagle Medium (high glucose), 50% RPMI Media 1640,10% fetal bovine serum (FBS), 1% 100× L-glutamine, 1% 100×Penicillin-Streptomycin, 1% 100× sodium pyruvate and 1% 100×MEMnon-essential amino acids. FBS was obtained from ATCC and all otherreagents were obtained from Invitrogen Corp. (Carlsbad, Calif., USA).Approximately 4-5×10(6) cells that had been cryopreserved in liquidnitrogen were rapidly thawed at 37° C. and transferred to a 175 cm²tissue culture flask containing 50 ml of growth media and then incubatedat 37° C. in a 5% CO₂ incubator. The growth media was replaced every 2-3days until the flask became 90% confluent, typically in 5-7 days. Topassage and expand the cell line, a 90% confluent flask was washed with10 ml of room temperature phosphate buffered saline (PBS) and the cellswere disassociated by adding 5 ml 1× Trypsin-EDTA (Invitrogen) andincubating at 37° C. until the cells detached from the surface of theflask. To inactivate the trypsin, 5 ml of growth media was added andthen the contents of the flask were centrifuged to pellet the cells. Thesupernatant was aspirated and the cell pellet was resuspended in 10 mlof growth media and the cell number determined using a hemocytometer.Approximately 1−3×10(6) cells per flask were seeded into 175 cm² flaskscontaining 50 ml of growth media and incubated at 37° C. in a 5% CO₂incubator. When the flasks reached 90% confluence, the above passagingprocess was repeated until sufficient cells had been obtained forimplantation into mice.

Seven to eight week old, female Crl:CD-1-nuBR (nude) mice were obtainedfrom Charles River Laboratories (Wilmington, Mass., USA). Animals werehoused 4-5/cage in micro-isolators, with a 12 hr/12 hr light/dark cycle,acclimated for at least 1 week prior to use and fed normal laboratorychow ad libitum. Studies were conducted on animals between 8 and 10weeks of age at implantation. To implant EMT6 tumor cells into nudemice, the cells were trypsinized as above, washed in PBS andresusupended at a concentration of 10×10(6) cells/ml in PBS. Using a 27gauge needle and 1 cc syringe, 0.1 ml of the cell suspension wasinjected subcutaneously into the flank of each nude mouse.

Tumors were then permitted to develop in vivo until the majority reached75-125 mm³ in tumor volume, which typically required 1 week followingimplantation. Animals with oblong, very small or large tumors werediscarded, and only animals carrying tumors that displayed consistentgrowth rates were selected for studies. Tumor volumes (V) werecalculated by caliper measurement of the width (W), length (L) andthickness (T) of tumors using the following formula: V=0.5236×(L×W×T).Animals were randomized into treatment groups so that each group hadmedian tumor volumes of ˜100 mm³ at the start of dosing.

To formulate Compound 3 in DRD, a stock solution of the test articlewere prepared by dissolving an appropriate amount of the compound indimethyl sulfoxide (DMSO) by sonication in an ultrasonic water bath. Asolution of 20% Cremophore RH40 (polyoxyl 40 hydrogenated castor oil;BASF Corp., Aktiengesellschaft, Ludwigshafen, Germany) in 5% dextrose inwater (Abbott Laboratories, North Chicago, Ill., USA) was also preparedby first heating 100% Cremophore RH40 at 50-60° C. until liquefied andclear, diluting 1:5 with 100% D5W, reheating again until clear and thenmixing well. This solution was stored at room temperature for up to 3months prior to use. To prepare a DRD formulation for dosing, the DMSOstock solution was diluted 1:10 with 20% Cremophore RH40. The final DRDformulation for dosing contained 10% DMSO, 18% Cremophore RH40, 3.6%dextrose, 68.4% water and the appropriate amount of test article.

Tumor-bearing animals were given a single intravenous (i.v.) bolusinjections of either DRD vehicle or Compound 3 formulated in DRD, bothat 10 mL per kg body weight. Then, 4-24 hr after drug treatment, tumorswere excised, cut in half and fixed overnight in 10% neutral-bufferedformalin. Each tumor was embedded in paraffin with the cut surfacesplaced downwards in the block, and rough cut until a complete sectionwas obtained. From each tumor, 5 μM serial sections were prepared andstained with hematoxylin and eosin. Slides were evaluated manually usinglight microscopy with a 10×10 square gridded reticle. The percentage ofnecrosis in a tumor was quantified at 200× magnification by scoring thetotal number of grid squares containing necrosis and the total number ofgrid squares containing viable tumor cells.

As shown in FIG. 19, a dramatic increase in necrotic tissue in thecenter of EMT6 tumors was observed after a single bolus injection of 25mg/kg body weight of Compound 3 relative to the baseline necrosisobserved in vehicle treated tumors. A near maximal 2.4 fold increase innecrosis was observed 4 hr after drug treatment. As would be expectedfor a vascular targeting mechanism of action, such rapid onset ofnecrosis is consistent with there being a loss of blood flow to tumorsresulting in hypoxia and tumor cell death.

Example 12 Compound 249 Depolymerizes Microtubules in CV-1 and HuvecCells

Depolymerizing microtubules not only kills dividing tumor cells but alsoinduces disruption of newly generated blood vessels in tumor. Thepotency of Compound 249 in depolymerizing microtubules was examined inAfrica green monkey kidney fibroblasts (CV1 cells) and primary humanumbilical vein endothelium cells (HUVEC cells). The cells were treatedwith drugs (1, 10, 100, and 1000 nM for CV-1 and 1, 5, 10, 50, 100 nMfor HUVEC) for 24 hr and fixed with 3% paraformaldehyde followed by coldmethanol treatment to preserve both microtubule structures anddepolymerized tubulin in the cytoplasm. The cells were stained withanti-tubulin antibody and subsequently fluorescent conjugated secondaryantibody to visualize microtubule networks or cytoplasmic tubulin withfluorescent microscopy. As shown in FIG. 20 and FIG. 21, Compound 249completely depolymerizes MT in a considerable proportion of CV1 cells at10 nM and HUVEC cells at 1 nM (about 10% for both cell lines; data notshown). At 100 nM for CV1 and 5 nM for HUVEC cells, microtubules werecompletely depolymerized in nearly 100% cells. Tubulin staining in thesecells was shown as cytoplasmic location and no microtubule structureswere found in those cells. Fragmented microtubules were found in HUVECcells treated with 1 nM Compound 249 (FIG. 21). Compound 249 is a potentmicrotubule depolymerizing drug and HUVEC cells are extremely sensitiveto Compound 249's anti-microtubule effect.

Example 13 Compound 174 Displays Anti-tumor and Vascular DisruptingActivities in a nude Mouse Tumor Model

The mouse mammary carcinoma cell line, EMT6 (ATCC #CRL-2755), wasobtained from the American Type Culture Collection (ATCC; Manassas, Va.,USA). The cell line was cultured in growth media prepared from 50%Dulbecco's Modified Eagle Medium (high glucose), 50% RPMI Media 1640,10% fetal bovine serum (FBS), 1% 100×L-glutamine, 1% 100×Penicillin-Streptomycin, 1% 100× sodium pyruvate and 1% 100×MEMnon-essential amino acids. FBS was obtained from ATCC and all otherreagents were obtained from Invitrogen Corp. (Carlsbad, Calif., USA).Approximately 4−5×10⁶ cells that had been cryopreserved in liquidnitrogen were rapidly thawed at 37° C. and transferred to a 175 cm²tissue culture flask containing 50 mL of growth media and then incubatedat 37° C. in a 5% CO₂ incubator. The growth media was replaced every 2-3days until the flask became 90% confluent, typically in 5-7 days. Topassage and expand the cell line, a 90% confluent flask was washed with10 mL of room temperature phosphate buffered saline (PBS) and the cellswere disassociated by adding 5 mL 1× Trypsin-EDTA (Invitrogen) andincubating at 37° C. until the cells detached from the surface of theflask. To inactivate the trypsin, 5 mL of growth media was added andthen the contents of the flask were centrifuged to pellet the cells. Thesupernatant was aspirated and the cell pellet was resuspended in 10 mLof growth media and the cell number determined using a hemocytometer.Approximately 1−3×10⁶ cells per flask were seeded into 175 cm² flaskscontaining 50 mL of growth media and incubated at 37° C. in a 5% CO₂incubator. When the flasks reached 90% confluence, the above passagingprocess was repeated until sufficient cells had been obtained forimplantation into mice.

Seven to eight week old, female Crl:CD-1-nuBR (nude) mice were obtainedfrom Charles River Laboratories (Wilmington, Mass., USA). Animals werehoused 4-5/cage in micro-isolators, with a 12 hr/12 hr light/dark cycle,acclimated for at least 1 week prior to use and fed normal laboratorychow ad libitum. Studies were conducted on animals between 8 and 10weeks of age at implantation. To implant EMT6 tumor cells into nudemice, the cells were trypsinized as above, washed in PBS andresusupended at a concentration of 10×10⁶ cells/mL in PBS. Using a 27gauge needle and 1 cc syringe, 0.1 mL of the cell suspension wasinjected subcutaneously into the flank of each nude mouse.

For the tumor growth delay assay, tumors were permitted to develop invivo until the majority reached 90-200 mm³ in tumor volume, whichtypically required 1 week following implantation. Alternatively, for theEvans Blue dye assay, tumors were permitted to develop in vivo until themajority reached 40-90 mm³ in tumor volume (to minimize the extent oftumor necrosis), which typically required 4-6 days followingimplantation. Animals with visibly necrotic, oblong, very small or verylarge tumors were discarded and only animals carrying tumors thatdisplayed consistent growth rates were selected for use. Tumor volumes(V) were calculated by caliper measurement of the width (W), length (L)and thickness (T) of tumors using the following formula:V=0.5236×(L×W×T). Animals were randomized into treatment groups so thatat the start of dosing each group had median tumor volumes of ˜125 mm³or ˜55 mm³ for the tumor growth delay or Evans Blue dye assays,respectively.

To formulate Compound 174 for dosing, the appropriate amount of compoundwas dissolved in 5% dextrose in water (D5W; Abbott Laboratories, NorthChicago, Ill., USA). Vehicle-treated animals were dosed with D5W.

Tumor-bearing animals were given single intravenous (i.v.) bolusinjections of either vehicle or Compound 174 at 10 mL per kg bodyweight. To measure the effect of the drug treatment on tumor growthrates, tumor volumes were measured 3 days after dosing (FIG. 22).

To conduct the Evans Blue dye assay (FIG. 23), tumor-bearing animalswere dosed with vehicle or test article at 0 hr, and then i.v. injectedwith 100 μL of a 1% (w/v) Evan's Blue dye (Sigma #E-2129; St. Louis,Mo., USA) solution in 0.9% NaCl at +1 hr. Tumors were excised at +4 hr,weighed and the tissue disassociated by incubation in 50 pL 1 N KOH at60° C. for 16 hr. To extract the dye, 125 μL of a 0.6 N phosphoric acidand 325□□L acetone were added, and the samples vigorously vortexed andthen microcentrifuged at 3000 RPM for 15 min to pellet cell debris. Theoptical absorbance of 200 μL of supernatant was then measured at 620 nMin a Triad spectrophotometer (Dynex Technologies, Chantilly, Va., USA).Background OD₆₂₀ values from similarly sized groups of vehicle or testarticle-treated animals that had not been injected with dye weresubtracted as background. OD₆₂₀ values were then normalized for tumorweight and dye uptake was calculated relative to vehicle-treated tumors.

The EMT6 mouse mammary carcinoma tumor model in nude mice is highlysensitive to treatment with Compound 174. As shown in FIG. 22, a singlei.v. bolus injection of 4.55 or 3.22 mg/kg body weight of Compound 174resulted in substantially decreased tumor growth over the subsequent 3days relative to vehicle-treated animals.

To examine the vascular disrupting activity of Compound 174, the EvansBlue dye assay was employed as a measurement of tumor blood volume(Graff et al., Eur J Cancer 36:1433-1440, 2000). Evans Blue dye makes acomplex with serum albumin by electrostatic interaction between thesulphonic acid group of the dye and the terminal cationic nitrogens ofthe lysine residues in albumin. The dye leaves the circulation veryslowly, principally by diffusion into extravascular tissues while stillbound to albumin. Albumin-dye complex taken up by tumors is located inthe extracellular space of non-necrotic tissue, and intracellular uptakeand uptake in necrotic regions is negligible. The amount of dye presentin a tumor is a measurement of the tumor blood volume and microvesselpermeability. As shown in FIG. 23, a single i.v. bolus injection of4.55, 3.22 or 2.28 mg/kg body weight of Compound 174 resulted insubstantially decreased tumor dye uptake relative to vehicle-treatedanimals. Such a decrease in dye penetration into the tumor is consistentwith there being a loss of blood flow to tumors due to blockage of tumorvasculature, consistent with a vascular disrupting mechanism of action.

All publications, patent applications, patents, and other documentscited herein are incorporated by reference in their entirety. In case ofconflict, the present specification, including definitions, willcontrol. In addition, the materials, methods, and examples areillustrative only and not intended to be limiting in any way.

We claim:
 1. A compound represented by structural formula (VI):

or a pharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, wherein: one of R_(k) or R_(l) is —H and the other isrepresented by the following formula:

the dashed line indicates that the bond is a single bond or a doublebond; X₃ and X₄ are each, independently, CH, N, CH₂, NR₁₆, O, or S; X₅and X₆ are each, independently, CR₂₉ or N; R₄ is an optionallysubstituted aryl or an optionally substituted heteroaryl; R₁₅ is H,halo, an optionally substituted alkyl, an optionally substitutedalkenyl, an optionally substituted alkynyl, an optionally substitutedcycloalkyl, an optionally substituted cycloalkenyl, an optionallysubstituted heterocyclyl, an optionally substituted aryl, an optionallysubstituted heteroaryl, an optionally substituted aralkyl, an optionallysubstituted heteraralkyl, cyano, nitro, guanadino, a haloalkyl, ahaloalkoxy, a heteroalkyl, —OR₁₇, —NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇,—C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇,—OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁; R₁₆ isH, an alkyl, a cycloalkyl, an aralkyl, —C(O)R, wherein R is an alkyl, acycloalkyl, or an aralkyl; R₂₉, for each occurrence, is independently, Hor a substituent; R₇ and R₈, for each occurrence, are, independently,—H, an optionally substituted alkyl, an optionally substituted alkenyl,an optionally substituted alkynyl, an optionally substituted cycloalkyl,an optionally substituted cycloalkenyl, an optionally substitutedheterocyclyl, an optionally substituted aryl, an optionally substitutedheteroaryl, an optionally substituted aralkyl, or an optionallysubstituted heteraralkyl; R₁₀ and R₁₁, for each occurrence, areindependently —H, an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, oran optionally substituted heteraralkyl; or R₁₀ and R₁₁, taken togetherwith the nitrogen to which they are attached, form an optionallysubstituted heterocyclyl or an optionally substituted heteroaryl; R₁₇,for each occurrence, is independently, an optionally substituted alkyl,an optionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl; and p is1 or
 2. 2. A compound represented by structural formula (VIII):

and pharmaceutically acceptable salts, solvates, clathrates, or prodrugsthereof, wherein: one of R₀ or R_(p) is —H and the other is representedby the following formula:

X₁ and X₂ are each, independently, CH or N; R₄ is an optionallysubstituted aryl or an optionally substituted heteroaryl; R₂₁ is halo,an optionally substituted alkyl, an optionally substituted alkenyl, anoptionally substituted alkynyl, an optionally substituted cycloalkyl, anoptionally substituted cycloalkenyl, an optionally substitutedheterocyclyl, an optionally substituted aryl, an optionally substitutedheteroaryl, an optionally substituted aralkyl, an optionally substitutedheteraralkyl, cyano, nitro, guanadino, a haloalkyl, a haloalkoxy, aheteroalkyl, —OR₁₇, —NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁,—NR₈C(O)R₇, —OP(O)(OR₇)₂, —SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇,—S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁; R₂₂, and R₂₃ areeach, independently, halo, an optionally substituted alkyl, anoptionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, an optionally substituted heteraralkyl, cyano,nitro, guanadino, a haloalkyl, a haloalkoxy, a heteroalkyl, —OR₇,—NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—OP(O)(OR₇)₂, —SP(O)(OR₇)₂, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇,—S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁; R₇ and R₈, for eachoccurrence, are, independently, —H, an optionally substituted alkyl, anoptionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl; R₁₀ andR₁₁, for each occurrence, are independently —H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, or an optionally substitutedheteraralkyl; or R₁₀ and R₁₁, taken together with the nitrogen to whichthey are attached, form an optionally substituted heterocyclyl or anoptionally substituted heteroaryl; R₁₇, for each occurrence, isindependently, an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, oran optionally substituted heteraralkyl; and p is 1 or
 2. 3. The compoundof claim 2, wherein R₄ is an optionally substituted phenyl.
 4. Thecompound of claim 2, wherein R₄ is an optionally substituted2,3-dihydro-benzo[1,4]dioxinyl, an optionally substituted biphenyl, anoptionally substituted 4-pyridinyl-phenyl, an optionally substitutedpyridinyl, an optionally substituted quinolinyl, an optionallysubstituted isoquinolinyl, an optionally substituted 1H-indolyl, anoptionally substituted oxazolyl, an optionally substitutedbenzo[1,3]dioxolyl, an optionally substituted pyridazinyl, an optionallysubstituted pyrimidinyl, or an optionally substituted benzofuranyl.
 5. Apharmaceutical composition, comprising a pharmaceutically acceptablecarrier and a compound of claim
 1. 6. The pharmaceutical composition ofclaim 5, further comprising one or more additional therapeutic agents.7. The pharmaceutical composition according to claim 6, wherein theadditional therapeutic agent is an anti-cancer agent.
 8. Apharmaceutical composition, comprising a pharmaceutically acceptablecarrier and a compound of claim
 2. 9. The pharmaceutical composition ofclaim 8, further comprising one or more additional therapeutic agents.10. The pharmaceutical composition according to claim 9, wherein theadditional therapeutic agent is an anti-cancer agent.